AOP-Wiki

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<div id="title">
<h2>AOP ID and Title:</h2>
<div class="title">AOP 298: Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</div>
<strong>Short Title: Increase in ROS leading to human treatment-resistant gastric cancer</strong>
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<h2>Graphical Representation</h2>
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<img src="https://www.aopwiki.org/system/dragonfly/production/2025/07/22/7o2vnwger7_GraphicalAbstract_AOP298_7_15_25.jpg" height="500" width="700" alt=""/>
<div id="authors">
<h2>Authors</h2>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Shihori Tanabe<sup>1)</sup>, Sabina Quader<sup>2)</sup>, Ryuichi Ono<sup>3)</sup>, Horacio Cabral<sup>4)</sup>, Ed Perkins<sup>5)</sup></span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px"><sup>1</sup>Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Japan</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px"><sup>2</sup>Innovation Centre of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Japan</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px"><sup>3</sup>Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Japan</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px"><sup>4</sup>Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Japan</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px"><sup>5</sup>Environmental Laboratory, US Army Engineer Research and Development Center, United States</span></span></p>
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<div id="status">
<h2>Status</h2>
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<thead class="thead-light">
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<th scope="col">Author status</th>
<th scope="col">OECD status</th>
<th scope="col">OECD project</th>
<th scope="col">SAAOP status</th>
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<tbody class="tbody-striped">
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<td>Open for comment. Do not cite</td>
<td>Under Review</td>
<td>1.58</td>
<td>Included in OECD Work Plan</td>
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<div id="abstract">
<h2>Abstract</h2>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">This AOP entitled “Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer” consists of MIE as </span>KE1115 “Increase, ROS” followed by KE1 as KE1754 “porcupine-induced Wnt secretion and Wnt signaling activation,” KE2 as KE1755 “beta-catenin activation,” KE3 as KE1457 “epithelial-mesenchymal transition (EMT),” and AO as KE1651 “human treatment-resistant gastric cancer.” ROS has multiple roles in disease, such as the development and progression of cancer or apoptotic induction, causing anti-tumor effects.<span style="font-family:Arial,Helvetica,sans-serif"> In this AOP, we focus on sustained levels of chronic reactive oxygen species (ROS) in inducing therapy resistance in human gastric cancer. Epithelial-mesenchymal transition (EMT), a cellular phenotypic change from epithelial to mesenchymal-like features, demonstrates cancer stem cell-like characteristics in human gastric cancer. EMT is induced by Wnt/beta-catenin signaling, providing the rationale to have Wnt secretion and beta-catenin activation as KE1 and KE2 on the AOP, respectively. The AOP might be useful for the development of anti-cancer drugs or the prediction of adverse effects of therapeutics, which are of possible regulatory relevance.</span></span></p>
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<div id="background">
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<div id="aop_summary">
<h2>Summary of the AOP</h2>
<h3>Events</h3>
<h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3>
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<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sequence</th>
<th scope="col">Type</th>
<th scope="col">Event ID</th>
<th scope="col">Title</th>
<th scope="col">Short name</th>
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</thead>
<tbody>
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<td></td>
<td>MIE</td>
<td>1115</td>
<td><a href="/events/1115">Increase, Reactive oxygen species</a></td>
<td>Increase, ROS</td>
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<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td>3</td>
<td>KE</td>
<td>1754</td>
<td><a href="/events/1754">Increase, porcupine-induced Wnt secretion and Wnt signaling activation</a></td>
<td>Increase, porcupine-induced Wnt secretion and Wnt signaling activation</td>
</tr>
<tr>
<td>4</td>
<td>KE</td>
<td>1755</td>
<td><a href="/events/1755">beta-catenin activation</a></td>
<td>beta-catenin activation</td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1457</td>
<td><a href="/events/1457">Epithelial Mesenchymal Transition</a></td>
<td>EMT</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td>6</td>
<td>AO</td>
<td>1651</td>
<td><a href="/events/1651">Treatment-resistant gastric cancer</a></td>
<td>Resistant gastric cancer</td>
</tr>
</tbody>
</table>
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<h3>Key Event Relationships</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Upstream Event</th>
<th scope="col">Relationship Type</th>
<th scope="col">Downstream Event</th>
<th scope="col">Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/relationships/3505">Increase, Reactive oxygen species</a></td>
<td>adjacent</td>
<td>Increase, porcupine-induced Wnt secretion and Wnt signaling activation</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
<tr>
<td><a href="/relationships/2070">Increase, porcupine-induced Wnt secretion and Wnt signaling activation</a></td>
<td>adjacent</td>
<td>beta-catenin activation</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
<tr>
<td><a href="/relationships/3199">beta-catenin activation</a></td>
<td>adjacent</td>
<td>Epithelial Mesenchymal Transition</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
<tr>
<td><a href="/relationships/3200">Epithelial Mesenchymal Transition</a></td>
<td>adjacent</td>
<td>Treatment-resistant gastric cancer</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
<tr>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
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</tbody>
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<h3>Stressors</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
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<th scope="col">Name</th>
<th scope="col">Evidence</th>
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<tbody class="tbody-striped">
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<td>Wnt</td>
<td>High</td>
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<td>WNT2</td>
<td>High</td>
</tr>
<tr>
<td>Porcupine</td>
<td>Moderate</td>
</tr>
<tr>
<td>Wntless</td>
<td>Moderate</td>
</tr>
<tr>
<td>Ionizing Radiation</td>
<td>Moderate</td>
</tr>
<tr>
<td>ferric nitrilotriacetate</td>
<td>Not Specified</td>
</tr>
</tbody>
</table>
</div>
<h4>Wnt</h4>
<p>WNT induces EMT (J. Zhang, Tian, & Xing, 2016). </p>
<h4>WNT2</h4>
<p>WNT2 induces EMT in cervical cancer (Zhou et al., 2016).</p>
<h4>Porcupine</h4>
<p><span style="font-family:times; font-size:14.0pt">Porcupine palmitoleates Wnt and facilitates the secretion of the Wnt ligand </span><!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:"ＭＳＰゴシック";background:aqua;mso-highlight:aqua;
mso-font-kerning:0pt;mso-ansi-language:EN-US;mso-fareast-language:JA;
mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Yu</Author><Year>2014</Year><RecNum>149</RecNum><DisplayText>(Yu
&amp; Virshup, 2014)</DisplayText><record><rec-number>149</rec-number><foreign-keys><key
app="EN" db-id="zfxrap00xevas9efewrvfezhzrxpw2a9zw50"
timestamp="1579487340">149</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Yu,
Jia</author><author>Virshup, David M</author></authors></contributors><titles><title>Updating
the Wnt pathways</title><secondary-title>Bioscience
Reports</secondary-title></titles><periodical><full-title>Bioscience
Reports</full-title></periodical><volume>34</volume><number>5</number><dates><year>2014</year></dates><isbn>0144-8463</isbn><urls><related-urls><url>https://doi.org/10.1042/BSR20140119</url></related-urls></urls><electronic-resource-num>10.1042/BSR20140119</electronic-resource-num><access-date>1/20/2020</access-date></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]--><span style="font-family:times; font-size:14.0pt">(</span><span style="font-family:ｍｓｐゴシック,sans-serif; font-size:12.0pt"><a href="#_ENREF_125" title="Yu, 2014 #149">Yu & Virshup, 2014</a></span><span style="font-family:times; font-size:14.0pt">)</span><!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:"ＭＳＰゴシック";background:aqua;mso-highlight:aqua;mso-font-kerning:
0pt;mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span
style='mso-element:field-end'></span></span><![endif]--> .</p>
<h4>Wntless</h4>
<p><span style="font-family:times; font-size:14.0pt">Wntless binds to and transport Wnt to the plasma membrane leading to the secretion of Wnt ligand </span><!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:"ＭＳＰゴシック";background:aqua;mso-highlight:aqua;
mso-font-kerning:0pt;mso-ansi-language:EN-US;mso-fareast-language:JA;
mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Yu</Author><Year>2014</Year><RecNum>149</RecNum><DisplayText>(Yu
&amp; Virshup, 2014)</DisplayText><record><rec-number>149</rec-number><foreign-keys><key
app="EN" db-id="zfxrap00xevas9efewrvfezhzrxpw2a9zw50"
timestamp="1579487340">149</key></foreign-keys><ref-type
name="Journal Article">17</ref-type><contributors><authors><author>Yu,
Jia</author><author>Virshup, David M</author></authors></contributors><titles><title>Updating
the Wnt pathways</title><secondary-title>Bioscience
Reports</secondary-title></titles><periodical><full-title>Bioscience
Reports</full-title></periodical><volume>34</volume><number>5</number><dates><year>2014</year></dates><isbn>0144-8463</isbn><urls><related-urls><url>https://doi.org/10.1042/BSR20140119</url></related-urls></urls><electronic-resource-num>10.1042/BSR20140119</electronic-resource-num><access-date>1/20/2020</access-date></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]--><span style="font-family:times; font-size:14.0pt">(</span><span style="font-family:ｍｓｐゴシック,sans-serif; font-size:12.0pt"><a href="#_ENREF_125" title="Yu, 2014 #149">Yu & Virshup, 2014</a></span><span style="font-family:times; font-size:14.0pt">)</span><!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:"ＭＳＰゴシック";background:aqua;mso-highlight:aqua;mso-font-kerning:
0pt;mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span
style='mso-element:field-end'></span></span><![endif]--><span style="font-family:times; font-size:14.0pt">.</span></p>
<h4>ferric nitrilotriacetate</h4>
<p><span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:helvetica neue,helvetica,arial,sans-serif; font-size:14px">Carcinogenic iron(III)-nitrilotriacetate induces reactive oxygen species production via trasfer of an electron to molecular oxygen to form reactive oxygen species [</span><span style="color:rgb(33, 33, 33); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:14px">Tsuchiya K, Akai K, Tokumura A, Abe S, Tamaki T, Takiguchi Y, Fukuzawa K.</span><span style="background-color:rgb(255, 255, 255); color:rgb(77, 128, 85); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:1.4rem"> </span><span style="background-color:rgb(255, 255, 255); color:rgb(77, 128, 85); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:1.4rem"> </span><span style="color:rgb(77, 128, 85); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:14px">Biochim Biophys Acta. 2005 Aug 30;1725(1):111-9. doi: 10.1016/j.bbagen.2005.05.001, </span><span style="color:rgb(33, 33, 33); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:14px">Akai K, Tsuchiya K, Tokumura A, Kogure K, Ueno S, Shibata A, Tamaki T, Fukuzawa K.</span><span style="background-color:rgb(255, 255, 255); color:rgb(77, 128, 85); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:1.4rem"> </span><span style="background-color:rgb(255, 255, 255); color:rgb(77, 128, 85); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:1.4rem"> </span><span style="color:rgb(77, 128, 85); font-family:blinkmacsystemfont,-apple-system,segoe ui,roboto,oxygen,ubuntu,cantarell,fira sans,droid sans,helvetica neue,sans-serif; font-size:14px">Free Radic Res. 2004 Sep;38(9):951-62. doi: 10.1080/1071576042000261945.].</span></p>
<p> </p>
</div>
<div id="overall_assessment">
<h2>Overall Assessment of the AOP</h2>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">1. Support for Biological Plausibility of KERs</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">MIE => KE1:<br />
Increase, ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:88px; vertical-align:bottom; width:416px">
<p style="text-align:left"><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">Biological Plausibility of the MIE => KE1 is moderate.<br />
Rationale: Sustained ROS caused by/causes DNA damage, which will alter several signaling pathways, including Wnt signaling. ROS stimulate inflammatory factor production and Wnt/</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">-catenin signaling. Macrophages accumulate </span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif"><span style="caret-color:#000000">in</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium"> injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion </span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">(</span></span><a href="#_ENREF_98" style="font-family: Century, serif; font-size: 12pt; color: blue; text-decoration: underline;" title="Vallée, 2018 #135"><span style="font-family:"ＭＳＰゴシック",sans-serif">Vallée & Lecarpentier, 2018</span></a><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">)</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">.</span></span></p>
Rationale: Sustained ROS caused by/causes DNA damage, which will alter several signaling pathways, including Wnt signaling. ROS stimulate inflammatory factor production and Wnt/</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">-catenin signaling. Macrophages accumulate </span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif">in</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium"> injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion </span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">(</span></span><a href="#_ENREF_98" style="font-family: Century, serif; font-size: 12pt; color: blue; text-decoration: underline;" title="Vallée, 2018 #135"><span style="font-family:"ＭＳＰゴシック",sans-serif">Vallée & Lecarpentier, 2018</span></a><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">)</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">.</span></span></p>
</td>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">KE1 => KE2:<br />
Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:145px; vertical-align:bottom; width:416px">
<p style="text-align:left"><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">Biological Plausibility of the KE1 => KE2 is moderate.<br />
Rationale: Secreted Wnt ligand stimulates Wnt/</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin signaling, in which </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">b</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black"> inactivation. GSK3</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">b</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black"> inactivation leads to </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin dephosphorylation, which avoids the ubiquitination of the </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">-catenin and </span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif"><span style="caret-color:#000000">stabilizes</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium"> the </span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin (Clevers & Nusse, 2012).</span></span></p>
Rationale: Secreted Wnt ligand stimulates Wnt/</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin signaling, in which </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">b</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black"> inactivation. GSK3</span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">b</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black"> inactivation leads to </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin dephosphorylation, which avoids the ubiquitination of the </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">-catenin and </span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif">stabilizes</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium"> the </span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin (Clevers & Nusse, 2012).</span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">KE2 => KE3:<br />
beta-catenin activation leads to Epithelial-mesenchymal transition (EMT)</span></span></span></span></p>
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<p style="text-align:left"><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">Biological Plausibility of the KE2 => KE3 is moderate.<br />
Rationale: </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">-catenin activation, of which </span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif"><span style="caret-color:#000000">mechanisms</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium"> include the stabilization of the dephosphorylated </span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin and translocation of </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">-catenin into the nucleus, </span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif"><span style="caret-color:#000000">induces</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium"> the formation of </span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb, and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman et al., 2017; Sohn et al., 2019; Yang W et al., 2019).</span></span></p>
Rationale: </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">-catenin activation, of which </span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif">mechanisms</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium"> include the stabilization of the dephosphorylated </span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin and translocation of </span></span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">-catenin into the nucleus, </span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif">induces</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium"> the formation of </span><span style="font-family:Symbol; font-size:12pt"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif; font-size:12pt"><span style="color:black">-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb, and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman et al., 2017; Sohn et al., 2019; Yang W et al., 2019).</span></span></p>
<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">EMT-related transcription factors, including Snail, ZEB, and Twist, are up-regulated in cancer cells (Diaz et al., 2014). The transcription factors such as Snail, ZEB, and Twist bind to the E-cadherin (CDH1) promoter and inhibit the CDH1 transcription via the consensus E-boxes (5’-CACCTG-3’ or 5’-CAGGTG-3’), which leads to EMT (Diaz et al., 2014).</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">KE3 => AO:<br />
Epithelial-mesenchymal transition (EMT) leads to treatment-resistant gastric cancer</span></span></span></span></p>
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~~<p style="text-align:left"><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">Biological Plausibility of the KE3 => AO is moderate.</span><br />~~
<span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">Rationale: Some populations of cells exhibiting EMT </span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif"><span style="caret-color:#000000">demonstrate</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium"> the feature of cancer stem cells (CSCs), which are related to cancer malignancy (Shibue & Weinberg, 2017; Tanabe, 2015a, 2015b; Tanabe et al., 2015). </span></p>
<p style="text-align:left"><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">Biological Plausibility of the KE3 => AO is moderate.</span><br />
<span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">Rationale: Some populations of cells exhibiting EMT </span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif">demonstrate</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium"> the feature of cancer stem cells (CSCs), which are related to cancer malignancy (Shibue & Weinberg, 2017; Tanabe, 2015a, 2015b; Tanabe et al., 2015). </span></p>
<p style="text-align:left"><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). </span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif"><span style="caret-color:#000000">The increase in</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium"> expression of enzymes that degrade the extracellular matrix components and the decrease in adhesion to the basement membrane in EMT induce the cell to escape from the basement membrane and metastasis (Smith & Bhowmick, 2016). Morphological changes observed during EMT are associated with therapy resistance (Smith & Bhowmick, 2016).  </span></p>
<p style="text-align:left"><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). </span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif">The increase in</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium"> expression of enzymes that degrade the extracellular matrix components and the decrease in adhesion to the basement membrane in EMT induce the cell to escape from the basement membrane and metastasis (Smith & Bhowmick, 2016). Morphological changes observed during EMT are associated with therapy resistance (Smith & Bhowmick, 2016).  </span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">2. Support for essentiality of KEs</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">MIE: Increase, ROS</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">Essentiality of the MIE is high.</span></span></span></span></p>
<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">Rationale for Essentiality of the MIE in the AOP: Sustained ROS contributes to the initiation and development of human gastric cancer (Gu et al., 2018).</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">KE1: Porcupine-induced Wnt secretion and Wnt signaling activation</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">Essentiality of the KE1 is moderate.<br />
Rationale for Essentiality of the KE1 in the AOP: The Wnt signaling activation is essential for the subsequent </span></span><span style="font-family:Symbol"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">-catenin activation and cancer resistance (Tanabe, 2018).</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">KE2:</span></span></span></span></p>
<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">beta-catenin activation</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">Essentiality of the KE2 is moderate.<br />
Rationale for Essentiality of the KE2 in the AOP: </span></span><span style="font-family:Symbol"><span style="color:black">beta</span></span><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">-catenin activation is essential for the Wnt-induced cancer resistance (Tanabe, 2018).</span></span></span></span></p>
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<p style="text-align:left"><span style="font-size:12pt"><span style="font-family:Century,serif"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:black">KE3: Epithelial-mesenchymal transition (EMT)</span></span></span></span></p>
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~~<p style="text-align:left"><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">Essentiality of the KE3 is moderate.</span><br />~~
<span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium">Rationale for Essentiality of the KE3 in the AOP: EMT is essential for the Wnt-induced cancer promotion and acquisition of resistance to anti-cancer drugs (Tanabe, 2018</span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif"><span style="caret-color:#000000">;</span></span><span style="color:#000000; font-family:ＭＳＰゴシック, sans-serif; font-size:medium"> Tanabe et al, 2020a, 2020b, 2023).</span></p>
<p style="text-align:left"><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">Essentiality of the KE3 is moderate.</span><br />
<span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium">Rationale for Essentiality of the KE3 in the AOP: EMT is essential for the Wnt-induced cancer promotion and acquisition of resistance to anti-cancer drugs (Tanabe, 2018</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif">;</span><span style="color:#000000; font-family:ＭＳＰゴシック,sans-serif; font-size:medium"> Tanabe et al, 2020a, 2020b, 2023).</span></p>
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<h3>Domain of Applicability</h3>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
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</thead>
<tbody class="tbody-striped">
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<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
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</tbody>
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</div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
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<tbody class="tbody-striped">
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<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">The AOP298 applies to <em>Homo sapiens </em>(human), all life stages, and both male and female.</span></span></p>
<p> </p>
<h3>Essentiality of the Key Events</h3>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Sustained ROS contributes to the initiation and development of human gastric cancer (Gu et al., 2018).</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Wnt signaling is involved in cancer malignancy<span style="color:#000000"> (</span><a href="#_ENREF_92" title="Tanabe, 2018 #126"><span style="color:#000000">Tanabe, 2018</span></a>).</span></span></p>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Upon stimulation with Wnt ligand to the Frizzled receptor, Wnt/beta-catenin signaling is activated. Wnt/beta-catenin consists of GSK3 beta inactivation, beta-catenin activation, and up-regulation of transcription factors such as Zeb, Twist, and Snail. The transcription factors Zeb, Twist and Snail relate to the activation of EMT-related genes. EMT is regulated with various gene networks (<a href="#_ENREF_89" title="Tanabe, 2015 #129"><span style="color:#000000">Tanabe, 2015</span></a>c, Tanabe et al, 2020a, 2020b).</span></span></p>
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<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:56px; text-align:center; vertical-align:middle; white-space:normal; width:232px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">Event</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">Direct Evidence</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">Indirect Evidence</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">No experimental evidence</span></span></span></td>
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<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; text-align:center; vertical-align:middle; white-space:normal; width:232px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">MIE: Increase, ROS</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">***</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">*</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">　</span></span></span></td>
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<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; text-align:center; vertical-align:middle; white-space:normal; width:232px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">KE1: Increase, porcupine-induced Wnt secretion and Wnt signaling activation</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">　</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">*</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">**</span></span></span></td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; text-align:center; vertical-align:middle; white-space:normal; width:232px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">KE2: beta-catenin activation</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">　</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">*</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">**</span></span></span></td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:80px; text-align:center; vertical-align:middle; white-space:normal; width:232px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">KE3: Epithelial-Mesenchymal Transition</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">　</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">*</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; text-align:center; vertical-align:middle; white-space:normal; width:237px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">**</span></span></span></td>
</tr>
</tbody>
</table>
<h3>Weight of Evidence Summary</h3>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">The Wnt signaling promotes EMT and cancer malignancy in colorectal cancer (Lazarova & Bordonaro, 2017). Although the potential pathways other than Wnt signaling exist in EMT induction and the mechanism underlaid cancer malignancy, Wnt signaling is one of the main pathways to induce EMT and cancer malignancy (Polakis, 2012).</span></span></p>
<table cellspacing="0" style="border-collapse:collapse; width:1165px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:68px; vertical-align:middle; white-space:normal; width:277px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">MIE => KE1:<br />
Increases in cellular ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:middle; white-space:normal; width:888px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">Empirical Support of the MIE => KE1 is moderate.<br />
Rationale: Production of ROS and DNA double-strand break cause the tissue damages (Gao et al., 2019).<br />
ROS-related signaling induces Wnt/b-catenin pathway activation (Pérez et al., 2017).</span></span></span></td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:68px; vertical-align:middle; white-space:normal; width:277px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">KE1 => KE2:<br />
Porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:888px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">Empirical Support of the KE1 => KE2 is moderate.<br />
Rationale: Dishevelled (DVL), a positive regulator of Wnt signaling, form the complex with FZD and lead to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (Clevers & Nusse, 2012; Jiang et al., 2015).<br />
Wnt binds to FZD and activate the Wnt signaling (Clevers & Nusse, 2012; Janda et al., 2012; Nile et al., 2017). Wnt binding towards FZD induce the formation of the protein complex with LRP5/6 and DVL, leading to the down-stream signaling activation including beta-catenin (Clevers & Nusse, 2012).</span></span></span></td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:68px; vertical-align:middle; white-space:normal; width:277px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">KE2 => KE3:<br />
beta-catenin activation leads to Epithelial-mesenchymal transition (EMT)</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:888px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">Empirical Support of the KE2 => KE3 is moderate.<br />
Rationale: The inhibition of c-MET, which is overexpressed in diffuse-type gastric cancer, induced increase in phosphorylated b-catenin, decrease in b-catenin and Snail (Sohn et al., 2019).<br />
The garcinol, that has anti-cancer effect, increases phosphorylated beta-catenin, decreases b-catenin and ZEB1/ZEB2, and inhibit EMT (Ahmad et al., 2012).<br />
The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in decrease in b-catenin and Twist expression in human glioblastoma cells (Yang W. et al., 2019).<br />
Histone deacetylase inhibitors effect on EMT-related transcription factors including ZEB, Twist and Snail (Wawruszak et al., 2019).<br />
Snail and Zeb induces EMT and suppress E-cadherin (CDH1) (Batlle et al., 2000; Diaz et al., 2014; Peinado et al., 2007).</span></span></span></td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:68px; vertical-align:middle; white-space:normal; width:277px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">KE3 => AO:<br />
Epithelial-mesenchymal transition (EMT) leads to Treatment-resistant gastric cancer</span></span></span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:middle; white-space:normal; width:888px"><span style="font-size:16px"><span style="color:black"><span style="font-family:游ゴシック">Empirical Support of the KE3 => AO is moderate.<br />
Rationale: EMT activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in doxorubicin resistance (Saxena et al., 2011; Shibue & Weinberg, 2017).<br />
TGFb-1 induced EMT results in the acquisition of cancer stem cell (CSC) like properties (Pirozzi et al., 2011; Shibue & Weinberg, 2017).<br />
Snail-induced EMT induces the cancer metastasis and resistance to dendritic cell-mediated immunotherapy (Kudo-Saito et al., 2009).<br />
Zinc finger E-box-binding homeobox (ZEB1)-induced EMT results in relief of miR-200-mediated repression of programmed cell death 1 ligand (PD-L1) expression, a major inhibitory ligand for the programmed cell death protein (PD-1) immune-checkpoint protein on CD8+ cytotoxic T lymphocyte (CTL), subsequently the CD8+ T cell immunosuppression and metastasis (Chen et al., 2014).</span></span></span></td>
</tr>
</tbody>
</table>
<h3>Quantitative Consideration</h3>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">Wnt signaling activates the CSCs to promote cancer malignancy <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:"Times New Roman",serif;
mso-fareast-font-family:"ＭＳＰゴシック";mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Reya</Author><Year>2005</Year><RecNum>124</RecNum><DisplayText>(Reya
&amp; Clevers, 2005)</DisplayText><record><rec-number>124</rec-number><foreign-keys><key
app="EN" db-id="zfxrap00xevas9efewrvfezhzrxpw2a9zw50"
timestamp="1570495668">124</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Reya,
Tannishtha</author><author>Clevers,
Hans</author></authors></contributors><titles><title>Wnt
signalling in stem cells and
cancer</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>843-850</pages><volume>434</volume><number>7035</number><dates><year>2005</year><pub-dates><date>2005/04/01</date></pub-dates></dates><isbn>1476-4687</isbn><urls><related-urls><url>https://doi.org/10.1038/nature03319</url></related-urls></urls><electronic-resource-num>10.1038/nature03319</electronic-resource-num></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(<a href="#_ENREF_70" title="Reya, 2005 #124">Reya & Clevers, 2005</a>)<!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:"Times New Roman",serif;
mso-fareast-font-family:"ＭＳＰゴシック";mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The responses in KEs related to Wnt signaling, Frizzled activation, GSK3beta inactivation, beta-catenin activation, Snail, Zeb, and Twist activation are dose-dependently related. The quantification of EMT and cancer malignancy would require further investigation.</span></span></p>
</div>
<div id="considerations_for_potential_applicaitons">
<h2>Considerations for Potential Applications of the AOP (optional)</h2>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">AOP entitled “Increase in reactive oxygen species (ROS) and chronic ROS leading to human treatment-resistant gastric cancer” might be utilized for the development and risk assessment of anti-cancer drugs. EMT is involved in the acquisition of drug resistance, which is one of the critical features of cancer malignancy. The assessment of the activity of the EMT network would serve as a prediction of the adverse effects of or responsiveness to anti-cancer drugs (Tanabe et al., 2023). The detection methods for increases in ROS in this AOP have future regulatory potentials to assess the human health effects of radiation or ROS-related diseases. The detection methods for human treatment-resistant gastric cancer have future regulatory potentials to diagnose the diseases.</span></span></p>
</div>
<div id="references">
<h2>References</h2>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_1"><span style="color:#000000">Ahmad, A., Sarkar, S. H., Bitar, B., Ali, S., Aboukameel, A., Sethi, S., . . . Sarkar, F. H. (2012). Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. <em>Mol Cancer Ther, 11</em>(10), 2193-2201. doi:10.1158/1535-7163.MCT-12-0232-T</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_4"><span style="color:#000000">Batlle, E., Sancho, E., Francí, C., Domínguez, D., Monfar, M., Baulida, J., & García de Herreros, A. (2000). The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. <em>Nature Cell Biology, 2</em>(2), 84-89. doi:10.1038/35000034</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_10"><span style="color:#000000">Chen, L., Gibbons, D. L., Goswami, S., Cortez, M. A., Ahn, Y.-H., Byers, L. A., . . . Qin, F. X.-F. (2014). Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. <em>Nature communications, 5</em>, 5241-5241. doi:10.1038/ncomms6241</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_14"><span style="color:#000000">Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. <em>Cell, 149</em>(6), 1192-1205. doi:10.1016/j.cell.2012.05.012</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_18"><span style="color:#000000">Diaz, V. M., Vinas-Castells, R., & Garcia de Herreros, A. (2014). Regulation of the protein stability of EMT transcription factors. <em>Cell Adh Migr, 8</em>(4), 418-428. doi:10.4161/19336918.2014.969998</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_25"><span style="color:#000000">Gao, Q., Zhou, G., Lin, S.-J., Paus, R., & Yue, Z. (2019). How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models. <em>Experimental dermatology, 28</em>(4), 413-418. doi:10.1111/exd.13846</span></a></span></span></p>
<p style="text-align:justify"><span style="color:#000000"><span style="font-size:18px">Gu, H., Huang, Y. Shen, Y. Liu, F. Zhou, Y. Jin, et al. (2018). Reactive Oxygen Species-Mediated Tumor Microenvironment Transformation: The Mechanism of Radioresistant Gastric Cancer. Oxid Med Cell Longev 2018 Vol. 2018 Pages 5801209. doi:10.1155/2018/5801209</span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_34"><span style="color:#000000">Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C., & Garcia, K. C. (2012). Structural basis of Wnt recognition by Frizzled. <em>Science, 337</em>(6090), 59-64. doi:10.1126/science.1222879</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_43"><span style="color:#000000">Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. </span></a><span style="color:#000000"><em>Cancer Cell, 15</em>(3), 195-206. doi: 10.1016/j.ccr.2009.01.023</span></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_47"><span style="color:#000000">Lazarova, D., & Bordonaro, M. (2017). ZEB1 Mediates Drug Resistance and EMT in p300-Deficient CRC. <em>Journal of Cancer, 8</em>(8), 1453-1459. doi:10.7150/jca.18762</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_61"><span style="color:#000000">Nile, A. H., Mukund, S., Stanger, K., Wang, W., & Hannoush, R. N. (2017). Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. </span></a><span style="color:#000000"><em>Proc Natl Acad Sci U S A, 114</em>(16), 4147-4152. doi:10.1073/pnas.1618293114</span></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_63"><span style="color:#000000">Pearlman, R. L., Montes de Oca, M. K., Pal, H. C., & Afaq, F. (2017). Potential therapeutic targets of epithelial-mesenchymal transition in melanoma. <em>Cancer Lett, 391</em>, 125-140. doi:10.1016/j.canlet.2017.01.029</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_64"><span style="color:#000000">Peinado, H., Olmeda, D., & Cano, A. (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? <em>Nat Rev Cancer, 7</em>(6), 415-428. doi:10.1038/nrc2131</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_65"><span style="color:#000000">Pérez, S., Taléns-Visconti, R., Rius-Pérez, S., Finamor, I., & Sastre, J. (2017). Redox signaling in the gastrointestinal tract. <em>Free radical biology & medicine, 104</em>, 75-103. doi:10.1016/j.freeradbiomed.2016.12.048</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_67"><span style="color:#000000">Pirozzi, G., Tirino, V., Camerlingo, R., Franco, R., La Rocca, A., Liguori, E., . . . Rocco, G. (2011). Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. <em>PLoS One, 6</em>(6), e21548-e21548. doi:10.1371/journal.pone.0021548</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_68"><span style="color:#000000">Polakis, P. (2012). Wnt signaling in cancer. <em>Cold Spring Harb Perspect Biol, 4</em>(5). doi:10.1101/cshperspect.a008052</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_70"><span style="color:#000000">Reya, T., & Clevers, H. (2005). Wnt signalling in stem cells and cancer. <em>Nature, 434</em>(7035), 843-850. doi:10.1038/nature03319</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_75"><span style="color:#000000">Saxena, M., Stephens, M. A., Pathak, H., & Rangarajan, A. (2011). Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. <em>Cell death & disease, 2</em>(7), e179-e179. doi:10.1038/cddis.2011.61</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_79"><span style="color:#000000">Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. <em>Nat Rev Clin Oncol, 14</em>(10), 611-629. doi:10.1038/nrclinonc.2017.44</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_81"><span style="color:#000000">Sohn, S. H., Kim, B., Sul, H. J., Kim, Y. J., Kim, H. S., Kim, H., . . . Zang, D. Y. (2019). INC280 inhibits Wnt/beta-catenin and EMT signaling pathways and its induce apoptosis in diffuse gastric cancer positive for c-MET amplification. <em>BMC Res Notes, 12</em>(1), 125. doi:10.1186/s13104-019-4163-x</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_86"><span style="color:#000000">Tanabe, S. (2013). Perspectives of gene combinations in phenotype presentation. <em>World journal of stem cells, 5</em>(3), 61-67. doi:10.4252/wjsc.v5.i3.61</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_88"><span style="color:#000000">Tanabe, S. (2015a). Origin of cells and network information. <em>World journal of stem cells, 7</em>(3), 535-540. doi:10.4252/wjsc.v7.i3.535</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_90"><span style="color:#000000">Tanabe, S. (2015b). Signaling involved in stem cell reprogramming and differentiation. <em>World journal of stem cells, 7</em>(7), 992-998. doi:10.4252/wjsc.v7.i7.992</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_89"><span style="color:#000000">Tanabe, S. (2015c). Overview of gene regulation in stem cell network to identify therapeutic targets utilizing genome databases. <em>Insights Stem Cells, 1</em>(1). </span></a></span></span></p>
<p style="text-align:justify"><span style="color:#000000"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">Tanabe, S. (2018). Wnt Signaling and Epithelial-Mesenchymal Transition Network in Cancer. Research Journal of Oncology, 2(2), 3.</span></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_94"><span style="color:#000000">Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2015). Regulated genes in mesenchymal stem cells and gastric cancer. <em>World journal of stem cells, 7</em>(1), 208-222. doi:10.4252/wjsc.v7.i1.208</span></a></span></span></p>
<p style="text-align:justify"><span style="color:#000000"><span style="font-size:18px">Tanabe, S., Quader, S., Cabral, H., <span style="font-family:Arial,Helvetica,sans-serif">& </span></span></span><span style="color:#000000"><span style="font-size:18px">Ono, R. (2020a). Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies. <em>Front. Pharmacol.</em> 11:904. doi: 10.3389/fphar.2020.00904</span></span></p>
<p style="text-align:justify"><span style="color:#000000"><span style="font-size:18px">Tanabe, S., Quader, S., Ono, R., Cabral, H., Aoyagi, K., Hirose, A., Yokozaki, H., & Sasaki, H. (2020b). Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer. <em>Cancers</em>, <em>12</em>(12), 3833. https://doi.org/10.3390/cancers12123833</span></span></p>
<p style="text-align:justify"><span style="color:#000000"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">Tanabe, S., Quader, S., Ono, R., Cabral, H., Aoyagi, K., Hirose, A., Perkins, E.J., Yokozaki, H., & Sasaki H. (2023). Regulation of Epithelial–Mesenchymal Transition Pathway and Artificial Intelligence-Based Modeling for Pathway Activity Prediction. <em>Onco</em>, 3(1):13-25. doi: 10.3390/onco3010002</span></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_98"><span style="color:#000000">Vallée, A., & Lecarpentier, Y. (2018). Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis. <em>Frontiers in immunology, 9</em>, 745-745. doi:10.3389/fimmu.2018.00745</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_104"><span style="color:#000000">Wawruszak, A., Kalafut, J., Okon, E., Czapinski, J., Halasa, M., Przybyszewska, A., . . . Stepulak, A. (2019). Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells. <em>Cancers (Basel), 11</em>(2). doi:10.3390/cancers11020148</span></a></span></span></p>
<p style="text-align:justify"><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif"><a name="_ENREF_110"><span style="color:#000000">Yang, W., Wu, P. F., Ma, J. X., Liao, M. J., Wang, X. H., Xu, L. S., . . . Yi, L. (2019). Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3beta/beta-catenin/twist pathway. <em>Cell Death Dis, 10</em>(3), 208. doi:10.1038/s41419-019-1449-9</span></a></span></span></p>
</div>
<div id="appendicies">
<h2>Appendix 1</h2>
<h3>List of MIEs in this AOP</h3>
<h4><a href="/events/1115">Event: 1115: Increase, Reactive oxygen species</a></h4>
<h5>Short Name: Increase, ROS</h5>
<h4>Key Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>reactive oxygen species biosynthetic process</td>
<td>reactive oxygen species</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/186">Aop:186 - unknown MIE leading to renal failure and mortality</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/213">Aop:213 - Inhibition of fatty acid beta oxidation leading to nonalcoholic steatohepatitis (NASH)</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/303">Aop:303 - Frustrated phagocytosis-induced lung cancer</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/383">Aop:383 - Inhibition of Angiotensin-converting enzyme 2 leading to liver fibrosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/382">Aop:382 - Angiotensin II type 1 receptor (AT1R) agonism leading to lung fibrosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/384">Aop:384 - Hyperactivation of ACE/Ang-II/AT1R axis leading to chronic kidney disease </a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/396">Aop:396 - Deposition of ionizing energy leads to population decline via impaired meiosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/409">Aop:409 - Frustrated phagocytosis leads to malignant mesothelioma</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/413">Aop:413 - Oxidation and antagonism of reduced glutathione leading to mortality via acute renal failure</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/416">Aop:416 - Aryl hydrocarbon receptor activation leading to lung cancer through IL-6 toxicity pathway</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/418">Aop:418 - Aryl hydrocarbon receptor activation leading to impaired lung function through AHR-ARNT toxicity pathway</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/386">Aop:386 - Deposition of ionizing energy leading to population decline via inhibition of photosynthesis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/387">Aop:387 - Deposition of ionising energy leading to population decline via mitochondrial dysfunction</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/319">Aop:319 - Binding to ACE2 leading to lung fibrosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/451">Aop:451 - Interaction with lung resident cell membrane components leads to lung cancer</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/476">Aop:476 - Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/492">Aop:492 - Glutathione conjugation leading to reproductive dysfunction via oxidative stress</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/497">Aop:497 - ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndrome</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/500">Aop:500 - Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/505">Aop:505 - Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/513">Aop:513 - Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/521">Aop:521 - Essential element imbalance leads to reproductive failure via oxidative stress</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/540">Aop:540 - Oxidative Stress in the Fish Ovary Leads to Reproductive Impairment via Reduced Vitellogenin Production</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/462">Aop:462 - Activation of reactive oxygen species leading the atherosclerosis</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/299">Aop:299 - Deposition of energy leading to population decline via DNA oxidation and follicular atresia</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/311">Aop:311 - Deposition of energy leading to population decline via DNA oxidation and oocyte apoptosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
~~<td><a href="/aops/325">Aop:325 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and cell death</a></td>~~
<td><a href="/aops/332">Aop:332 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell growth</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
~~<td><a href="/aops/332">Aop:332 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell proliferation</a></td>~~
<td><a href="/aops/331">Aop:331 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and cell death</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
~~<td><a href="/aops/324">Aop:324 - Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and cell death</a></td>~~
<td><a href="/aops/326">Aop:326 - Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation and reduced cell proliferation</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/331">Aop:331 - Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and reduced cell proliferation</a></td>
~~<td>MolecularInitiatingEvent</td>~~
~~</tr>~~
~~<tr>~~
~~<td><a href="/aops/326">Aop:326 - Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell death</a></td>~~
~~<td>MolecularInitiatingEvent</td>~~
~~</tr>~~
~~<tr>~~
<td><a href="/aops/333">Aop:333 - Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation</a></td>
<td><a href="/aops/333">Aop:333 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell proliferation</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/327">Aop:327 - Excessive reactive oxygen species production leading to mortality (1)</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/328">Aop:328 - Excessive reactive oxygen species production leading to mortality (2)</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/329">Aop:329 - Excessive reactive oxygen species production leading to mortality (3)</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/330">Aop:330 - Excessive reactive oxygen species production leading to mortality (4)</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/26">Aop:26 - Calcium-mediated neuronal ROS production and energy imbalance</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/534">Aop:534 - Succinate dehydrogenase (SDH) inhibition leads to cancer through oxidative stress</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/273">Aop:273 - Mitochondrial complex inhibition leading to liver injury</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/488">Aop:488 - Increased reactive oxygen species production leading to decreased cognitive function</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/298">Aop:298 - Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/27">Aop:27 - Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/511">Aop:511 - The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects </a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/207">Aop:207 - NADPH oxidase and P38 MAPK activation leading to reproductive failure in Caenorhabditis elegans</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/423">Aop:423 - Toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway </a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/481">Aop:481 - AOPs of amorphous silica nanoparticles: ROS-mediated oxidative stress increased respiratory dysfunction and diseases.</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/282">Aop:282 - Adverse outcome pathway on photochemical toxicity initiated by light exposure</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/569">Aop:569 - Decreased DNA methylation of FAM50B/PTCHD3 leading to IQ loss of children via PI3K-Akt pathway</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/324">Aop:324 - Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation and cell death</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/325">Aop:325 - Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation and reduced cell growth</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/595">Aop:595 - Emerging OPFRS reproductive outcome pathway</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/596">Aop:596 - Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell injury/death</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/598">Aop:598 - Excessive reactive oxygen species leading to growth inhibition via protein oxidation and reduced cell proliferation</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/599">Aop:599 - Excessive reactive oxygen species leading to growth inhibition via fatty acid oxidation and cell injury/death</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/600">Aop:600 - Excessive reactive oxygen species leading to growth inhibition via fatty acid oxidation and reduced cell growth</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/601">Aop:601 - Excessive reactive oxygen species leading to growth inhibition via fatty acid oxidation and reduced cell proliferation</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/602">Aop:602 - Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/603">Aop:603 - Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell cycle disruption</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
<tr>
<td><a href="/aops/608">Aop:608 - Thyroid Hormone Excess Leading to Reduced, Swimming Performance via Hypomyelination</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/613">Aop:613 - Peroxisome proliferator-activated receptor alpha activation leading to early life stage mortality via increased reactive oxygen species production</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/622">Aop:622 - Calcineurin inhibitor induced nephrotoxicity leading to kidney failure</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Vertebrates</td>
<td>Vertebrates</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>human and other cells in culture</td>
<td>human and other cells in culture</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mouse</td>
<td>Mus musculus</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>crustaceans</td>
<td>Daphnia magna</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=35525" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Lemna minor</td>
<td>Lemna minor</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=4472" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>zebrafish</td>
<td>Danio rerio</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=7955" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
<tr>
<td>Mixed</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<p>ROS is a normal constituent found in all organisms, <em>lifestages, and sexes.</em></p>
<h4>Key Event Description</h4>
<p>Biological State: increased reactive oxygen species (ROS)</p>
<p>Biological compartment: an entire cell -- may be cytosolic, may also enter organelles.</p>
<p>Reactive oxygen species (ROS) are O<sub>2</sub>- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017). <br />
However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015). </p>
<div>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Reactive oxygen species (ROS) refers to the chemical species superoxide, hydrogen peroxide, and their secondary reactive products. In the biological context, ROS are signaling molecules with important roles in cell energy metabolism, cell proliferation, and fate. Therefore, balancing ROS levels at the cellular and tissue level is an important part of many biological processes. Disbalance, mainly an increase in ROS levels, can cause cell dysfunction and irreversible cell damage.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS are produced from both exogenous stressors and normal endogenous cellular processes, such as the mitochondrial electron transport chain (ETC). Inhibition of the ETC can result in the accumulation of ROS. Exposure to chemicals, heavy metal ions, or ionizing radiation can also result in increased production of ROS. Chemicals and heavy metal ions can deplete cellular antioxidants reducing the cell’s ability to control cellular ROS and resulting in the accumulation of ROS. Cellular antioxidants include glutathione (GSH), protein sulfhydryl groups, superoxide dismutase (SOD). </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS are radicals, ions, or molecules that have a single unpaired electron in their outermost shell of electrons, which can be categorized into two groups: free oxygen radicals and non-radical ROS [Liou et al., 2010]. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><Free oxygen radicals></span></span></p>
<div>
<table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none">
<tbody>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">superoxide</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O<sub>2</sub>·<sup>-</sup></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">hydroxyl radical</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">·OH</span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">nitric oxide</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">NO·</span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">organic radicals</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">R·</span></span></p>
</td>
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<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">peroxyl radicals</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROO·</span></span></p>
</td>
</tr>
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<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">alkoxyl radicals</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RO·</span></span></p>
</td>
</tr>
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<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">thiyl radicals</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RS·</span></span></p>
</td>
</tr>
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<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">sulfonyl radicals</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS·</span></span></p>
</td>
</tr>
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<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">thiyl peroxyl radicals</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RSOO·</span></span></p>
</td>
</tr>
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<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">disulfides</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RSSR</span></span></p>
</td>
</tr>
</tbody>
</table>
</div>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><Non-radical ROS></span></span></p>
<div>
<table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none">
<tbody>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">hydrogen peroxide</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">H<sub>2</sub>O<sub>2</sub></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">singlet oxygen</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><sup>1</sup>O<sub>2</sub></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ozone/trioxygen</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O<sub>3</sub></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">organic hydroperoxides</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROOH</span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">hypochlorite</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ClO<sup>-</sup></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">peroxynitrite</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ONOO<sup>-</sup></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">nitrosoperoxycarbonate anion</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O=NOOCO<sub>2</sub><sup>-</sup></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">nitrocarbonate anion</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O<sub>2</sub>NOCO<sub>2</sub><sup>-</sup></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">dinitrogen dioxide</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">N<sub>2</sub>O<sub>2</sub></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">nitronium</span></span></p>
</td>
<td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">NO<sub>2</sub><sup>+</sup></span></span></p>
</td>
</tr>
<tr>
<td colspan="2" style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:580px">
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">highly reactive lipid- or carbohydrate-derived carbonyl compounds</span></span></p>
</td>
</tr>
</tbody>
</table>
</div>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Potential sources of ROS include NADPH oxidase, xanthine oxidase, mitochondria, nitric oxide synthase, cytochrome P450, lipoxygenase/cyclooxygenase, and monoamine oxidase [Granger et al., 2015]. ROS are generated through NADPH oxidases consisting of p47<sup>phox</sup> and p67<sup>phox</sup>. ROS are generated through xanthine oxidase activation in sepsis [Ramos et al., 2018]. Arsenic produces ROS [Zhang et al., 2011]. Mitochondria-targeted paraquat and metformin mediate ROS production [Chowdhury et al., 2020]. ROS are generated by bleomycin [Lu et al., 2010]. Radiation induces dose-dependent ROS production [Ji et al., 2019]. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS are generated in the course of cellular respiration, metabolism, cell signaling, and inflammation [Dickinson and Chang 2011; Egea et al. 2017]. Hydrogen peroxide is also made by the endoplasmic reticulum in the course of protein folding. Nitric oxide (NO) is produced at the highest levels by nitric oxide synthase in endothelial cells and phagocytes. NO production is one of the main mechanisms by which phagocytes kill bacteria [Wang et al., 2017]. The other species are produced by reactions with superoxide or peroxide, or by other free radicals or enzymes.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS activity is principally local. Most ROS have short half-lives, ranging from nano- to milliseconds, so diffusion is limited, while reactive nitrogen species (RNS) nitric oxide or peroxynitrite can survive long enough to diffuse across membranes [Calcerrada et al. 2011]. Consequently, local concentrations of ROS are much higher than average cellular concentrations, and signaling is typically controlled by colocalization with redox buffers [Dickinson and Chang 2011; Egea et al. 2017]. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Although their existence is limited temporally and spatially, ROS interact with other ROS or with other nearby molecules to produce more ROS and participate in a feedback loop to amplify the ROS signal, which can increase RNS. Both ROS and RNS also move into neighboring cells, and ROS can increase intracellular ROS signaling in neighboring cells [Egea et al. 2017].</span></span></p>
<p>In the primary event, photoreactive chemicals are excited by the absorption of photon energy.  The energy of the photoactivated chemicals transfer to oxygen and then generates the reactive oxygen species (ROS), including superoxide (O<sub>2</sub><sup>−</sup>) via type I reaction and singlet oxygen (<sup>1</sup>O<sub>2</sub>) via type II reaction, as principal intermediate species in phototoxic reaction (Foote, 1991, Onoue et al. , 2009).</p>
</div>
<h4>How it is Measured or Detected</h4>
<p>Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies.</p>
<p>Yuan, Yan, et al., (2013) described ROS monitoring by using H<sub>2</sub>-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H<sub>2</sub>-DCF-DA (50 µmol/L final concentration) for 30 min in the dark at 37°C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm.</p>
<p>Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013).</p>
<p>Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.</p>
<p>On the basis of the pathogenesis of drug-induced phototoxicity, a reactive oxygen species (ROS) assay was proposed to evaluate the phototoxic risk of chemicals. The ROS assay can monitor generation of ROS, such as singlet oxygen and superoxide, from photoirradiated chemicals, and the ROS data can be used to evaluate the photoreactivity of chemicals (Onoue et al. , 2014, Onoue et al. , 2013, Onoue and Tsuda, 2006).  The ROS assay is a recommended approach by guidelines to evaluate the phototoxic risk of chemicals (ICH, 2014, PCPC, 2014).</p>
<div>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><Direct detection></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Many fluorescent compounds can be used to detect ROS, some of which are specific, and others are less specific. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・ROS can be detected by fluorescent probes such as <em>p</em>-methoxy-phenol derivative [Ashoka et al., 2020].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Chemiluminescence analysis can detect the superoxide, where some probes have a wider range for detecting hydroxyl radical, hydrogen peroxide, and peroxynitrite [Fuloria et al., 2021].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・ROS in the blood can be detected using superparamagnetic iron oxide nanoparticles (SPION)-based biosensor [Lee et al., 2020].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) can be detected with a colorimetric probe, which reacts with H<sub>2</sub>O<sub>2</sub> in a 1:1 stoichiometry to produce a bright pink colored product, followed by the detection with a standard colorimetric microplate reader with a filter in the 540-570 nm range.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・The levels of ROS can be quantified using multiple-step amperometry using a stainless steel counter electrode and non-leak Ag|AgCl reference node [Flaherty et al., 2017].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Singlet oxygen can be measured by monitoring the bleaching of <em>p</em>-nitrosodimethylaniline at 440 nm using a spectrophotometer with imidazole as a selective acceptor of singlet oxygen [Onoue et al., 2014].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><Indirect Detection></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Alternative methods involve the detection of redox-dependent changes to cellular constituents such as proteins, DNA, lipids, or glutathione [Dickinson and Chang 2011; Wang et al. 2013; Griendling et al. 2016]. However, these methods cannot generally distinguish between the oxidative species behind the changes and cannot provide good resolution for the kinetics of oxidative activity.</span></span></p>
</div>
<h4>References</h4>
<p>Akai, K., et al. (2004). "Ability of ferric nitrilotriacetate complex with three pH-dependent conformations to induce lipid peroxidation." Free Radic Res. Sep;38(9):951-62. doi: 10.1080/1071576042000261945</p>
<p>Ashoka, A. H., et al. (2020). "Recent Advances in Fluorescent Probes for Detection of HOCl and HNO." ACS omega, 5(4), 1730-1742. doi:10.1021/acsomega.9b03420</p>
<p>B.H. Park, S.M. Fikrig, E.M. Smithwick Infection and nitroblue tetrazolium reduction by neutrophils: a diagnostic aid Lancet, 2 (1968), pp. 532-534</p>
<p>Bedard, Karen, and Karl-Heinz Krause. 2007. “The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.” Physiological Reviews 87 (1): 245–313.</p>
<p>Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. “Oxidative Stress and Male Infertility.” Nature Reviews. Urology 14 (8): 470–85.</p>
<p>Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. “Reactive Oxygen Species: From Health to Disease.” Swiss Medical Weekly 142 (August): w13659.</p>
<p>Calcerrada, P., et al. (2011). "Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications." Curr Pharm Des 17(35): 3905-3932.</p>
<p>Chattopadhyay, Sukumar, et al. "Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants." Toxicology letters 136.1 (2002): 65-76.</p>
<p>Chowdhury, A. R., et al. (2020). "Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon." Redox Biol. doi: 10.1016/j.redox.2020.101606. PMID: 32604037; PMCID: PMC7327929.</p>
<p>Dickinson, B. C. and Chang C. J. (2011). "Chemistry and biology of reactive oxygen species in signaling or stress responses." Nature chemical biology 7(8): 504-511.</p>
<p>Drew, Barry, and Christiaan Leeuwenburgh. 2002. “Aging and the Role of Reactive Nitrogen Species.” Annals of the New York Academy of Sciences 959 (April): 66–81.</p>
<p>Egea, J., et al. (2017). "European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)." Redox biology 13: 94-162.</p>
<p>Flaherty, R. L., et al. (2017). "Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer." Breast Cancer Research, 19(1), 1–13. https://doi.org/10.1186/s13058-017-0823-8</p>
<p>Foote CS. Definition of type I and type II photosensitized oxidation. Photochem Photobiol. 1991;54:659.</p>
<p>Fuloria, S., et al. (2021). "Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer." Antioxidants (Basel, Switzerland) 10(1) 128. doi:10.3390/antiox10010128</p>
<p>Go, Y. M. and Jones, D. P. (2013). "The redox proteome." J Biol Chem 288(37): 26512-26520.</p>
<p>Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. “Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.” Free Radical Biology & Medicine 44 (7): 1295–1304.</p>
<p>Granger, D. N. and Kvietys, P. R. (2015). "Reperfusion injury and reactive oxygen species: The evolution of a concept" Redox Biol. doi: 10.1016/j.redox.2015.08.020. PMID: 26484802; PMCID: PMC4625011.</p>
<p>Griendling, K. K., et al. (2016). "Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association." Circulation research 119(5): e39-75.</p>
<p>Griendling, Kathy K., Rhian M. Touyz, Jay L. Zweier, Sergey Dikalov, William Chilian, Yeong-Renn Chen, David G. Harrison, Aruni Bhatnagar, and American Heart Association Council on Basic Cardiovascular Sciences. 2016. “Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.” Circulation Research 119 (5): e39–75.</p>
<p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p>
<p>Itziou, A., et al. (2011). "In vivo and in vitro effects of metals in reactive oxygen species production, protein carbonylation, and DNA damage in land snails Eobania vermiculata." Archives of Environmental Contamination and Toxicology, 60(4), 697–707. https://doi.org/10.1007/s00244-010-9583-5</p>
<p>Ji, W. O., et al. "Quantitation of the ROS production in plasma and radiation treatments of biotargets." Sci Rep. 2019 Dec 27;9(1):19837. doi: 10.1038/s41598-019-56160-0. PMID: 31882663; PMCID: PMC6934759.</p>
<p>Kruk, J. and Aboul-Enein, H. Y. (2017). "Reactive Oxygen and Nitrogen Species in Carcinogenesis: Implications of Oxidative Stress on the Progression and Development of Several Cancer Types." Mini-Reviews in Medicinal Chemistry, 17:11. doi:10.2174/1389557517666170228115324</p>
<p>Lee, D. Y., et al. (2020). "PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood." Theranostics, 10(5), 1997-2007. doi:10.7150/thno.39662</p>
<p>Li, Z., et al. (2020). "Inhibition of MiR-25 attenuates doxorubicin-induced apoptosis, reactive oxygen species production and DNA damage by targeting pten." International Journal of Medical Sciences, 17(10), 1415–1427. https://doi.org/10.7150/ijms.41980</p>
<p>Liou, G. Y. and Storz, P. "Reactive oxygen species in cancer." Free Radic Res. 2010 May;44(5):479-96. doi:10.3109/10715761003667554. PMID: 20370557; PMCID: PMC3880197.</p>
<p>Lu, Y., et al. (2010). "Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production." American journal of respiratory cell and molecular biology, 42(4), 432–441. https://doi.org/10.1165/rcmb.2009-0002OC</p>
<p>Onoue, S., et al. (2013). "Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation." J Appl Toxicol. 33(11):1241-50. doi: 10.1002/jat.2776. Epub 2012 Jun 13. PMID: 22696462.</p>
<p>Onoue S, Hosoi K, Toda T, Takagi H, Osaki N, Matsumoto Y, et al. Intra-/inter-laboratory validation study on reactive oxygen species assay for chemical photosafety evaluation using two different solar simulators. Toxicology in vitro : an international journal published in association with BIBRA. 2014;28:515-23.</p>
<p>Onoue S, Hosoi K, Wakuri S, Iwase Y, Yamamoto T, Matsuoka N, et al. Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation. Journal of applied toxicology : JAT. 2013;33:1241-50.</p>
<p>Onoue S, Kawamura K, Igarashi N, Zhou Y, Fujikawa M, Yamada H, et al. Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: classification criteria and application to drug candidates. J Pharm Biomed Anal. 2008;47:967-72.</p>
<p>Onoue S, Seto Y, Gandy G, Yamada S. Drug-induced phototoxicity; an early<em> in vitro</em> identification of phototoxic potential of new drug entities in drug discovery and development. Current drug safety. 2009;4:123-36.</p>
<p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p>
<p>Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen.</p>
<p>Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier.</p>
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<p>Ramos, M. F. P., et al. (2018). "Xanthine oxidase inhibitors and sepsis." Int J Immunopathol Pharmacol. 32:2058738418772210. doi:10.1177/2058738418772210</p>
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<h3>List of Key Events in the AOP</h3>
<h4><a href="/events/1754">Event: 1754: Increase, porcupine-induced Wnt secretion and Wnt signaling activation</a></h4>
<h5>Short Name: Increase, porcupine-induced Wnt secretion and Wnt signaling activation</h5>
<h4>Key Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Wnt protein secretion</td>
<td>protein-serine O-palmitoleoyltransferase porcupine</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/298">Aop:298 - Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Stressors</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Name</th></tr>
</thead>
<tbody>
<tr><td>Radiation</td></tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Mus musculus</td>
<td>Mus musculus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Oligomerization of FZD and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) activates Wnt/beta-catenin signaling in <em>Homo sapiens</em> (<a href="#_ENREF_31" title="Hua, 2018 #96">Hua et al., 2018</a></span></span><span style="font-family:times; font-size:14.0pt"><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">)<em>.</em></span></span> </span><!--[if supportFields]><span lang=EN-US style='font-size:
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style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span
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<h4>Key Event Description</h4>
<p>Porcupine, which is a trans-membrane endoplasmic reticulum O-acyl transferase, is important for the secretion of Wnt ligands(<a href="#_ENREF_72" title="Saha, 2016 #126">Saha et al., 2016a</a>). WNTs are secreted proteins that contain 22-24 conserved cysteine residues (<a href="#_ENREF_23" title="Foulquier, 2018 #40">Foulquier et al., 2018</a>). The WNT molecules consist of molecular families including WNT1, WNT2, WNT2B/WNT13, WNT3, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT10B, WNT11, and WNT16. (<a href="#_ENREF_14" title="Clevers, 2012 #10">Clevers & Nusse, 2012</a>; <a href="#_ENREF_37" title="Katoh, 2001 #5">M. Katoh, 2001</a>; <a href="#_ENREF_44" title="Kusserow, 2005 #9">Kusserow et al., 2005</a>) </p>
<p></p>
<p>Wnt proteins consist of 350-400 amino acids (<a href="#_ENREF_74" title="Saito-Diaz, 2013 #79">Saito-Diaz et al., 2013</a>).</p>
<p>WNT ligands are known to trigger at least three different downstream signaling cascades including canonical WNT/beta-catenin signaling pathway, non-canonical WNT/Ca<sup>2+</sup> pathway, and planer cell polarity (PCP) pathway(<a href="#_ENREF_17" title="De, 2011 #87">De, 2011</a>; <a href="#_ENREF_46" title="Lai, 2009 #86">Lai, Chien, & Moon, 2009</a>; <a href="#_ENREF_106" title="Willert, 2012 #85">Willert & Nusse, 2012</a>). WNTs bind to Frizzled proteins, which are seven-pass transmembrane receptors with an extracellular N-terminal cysteine-rich domain (<a href="#_ENREF_5" title="Bhanot, 1996 #27">Bhanot et al., 1996</a>; <a href="#_ENREF_13" title="Clevers, 2006 #25">Clevers, 2006</a>). Wnt signaling begins with the binding of Wnt ligand towards the Frizzled receptors (<a href="#_ENREF_58" title="Mohammed, 2016 #41">Mohammed et al., 2016</a>). </p>
<p></p>
<p>Wnt ligands bind to Frizzled (FZD) receptors which are seven transmembrane-domain protein receptors (<a href="#_ENREF_61" title="Nile, 2017 #92">Nile, Mukund, Stanger, Wang, & Hannoush, 2017</a>). At least 10 FZD receptors are identified in human cells. FZD receptor is activated by Wnt ligand binding (<a href="#_ENREF_51" title="MacDonald, 2009 #93">MacDonald, Tamai, & He, 2009</a>). </p>
<h4>How it is Measured or Detected</h4>
<ul>
<li>Secretion of WNT requires a number of other dedicated factors including the sortin receptor Wntless (WLS), which binds to Wnt and escorts it to the cell surface (<a href="#_ENREF_3" title="Banziger, 2006 #80">Banziger et al., 2006</a>; <a href="#_ENREF_12" title="Ching, 2006 #81">Ching & Nusse, 2006</a>)</li>
<li>Wnt signaling is activated by the gene mutations of the signaling components (<a href="#_ENREF_118" title="Ziv, 2017 #83">Ziv et al., 2017</a>).</li>
<li>Wnt1, Wnt3a, and Wnt5a protein expression are measured by immunoblotting using antibodies for Wnt1, Wnt3a, and Wnt5a, respectively (<a href="#_ENREF_20" title="Du, 2016 #84">J. Du et al., 2016</a>; <a href="#_ENREF_100" title="Wang, 2017 #72">B. Wang et al., 2017</a>).</li>
<li>WNT2, of which expression is detected by quantitative PCR, immunoblotting, and immunohistochemistry, induces EMT (<a href="#_ENREF_117" title="Zhou, 2016 #73">Zhou et al., 2016</a>).</li>
<li>Frizzled receptor protein level on the cell surface is measured by flow cytometry with pan-FZD antibody (<a href="#_ENREF_36" title="Jiang, 2015 #95">Jiang et al., 2015</a>; <a href="#_ENREF_113" title="Zeng, 2018 #94">Zeng et al., 2018</a>). DVL protein level is measured by immunoblotting with anti-DVL2 antibodies (<a href="#_ENREF_113" title="Zeng, 2018 #94">Zeng et al., 2018</a>).</li>
<li>Fzd mRNA level is measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) (<a href="#_ENREF_113" title="Zeng, 2018 #94">Zeng et al., 2018</a>).</li>
<li>The up-regulation of WNT ligand expression occurs in <em>Homo sapiens</em> (<a href="#_ENREF_100" title="Wang, 2017 #72">B. Wang et al., 2017</a>).</li>
<li><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px">The Wnt genes play an important role in the secretion from cells, glycosylation, and tight association with the cell surface and extracellular matrix in <em>Drosophila melanogaster</em> (Willert & Nusse, 2012).</span></span> </li>
</ul>
<h4>References</h4>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Banziger, C., Soldini, D., Schutt, C., Zipperlen, P., Hausmann, G., & Basler, K. (2006). Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. <em>Cell, 125</em>(3), 509-522. doi:10.1016/j.cell.2006.02.049</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Bhanot, P., Brink, M., Samos, C. H., Hsieh, J.-C., Wang, Y., Macke, J. P., . . . Nusse, R. (1996). A new member of the frizzled family from Drosophila functions as a Wingless receptor. <em>Nature, 382</em>, 225. doi:10.1038/382225a0</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Ching, W., & Nusse, R. (2006). A dedicated Wnt secretion factor. <em>Cell, 125</em>(3), 432-433. doi:10.1016/j.cell.2006.04.018</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. <em>Cell, 127</em>(3), 469-480. doi:10.1016/j.cell.2006.10.018</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. <em>Cell, 149</em>(6), 1192-1205. doi:10.1016/j.cell.2012.05.012</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">De, A. (2011). Wnt/Ca2+ signaling pathway: a brief overview. <em>Acta Biochim Biophys Sin (Shanghai), 43</em>(10), 745-756. doi:10.1093/abbs/gmr079</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Du, J., Zu, Y., Li, J., Du, S., Xu, Y., Zhang, L., . . . Yang, C. (2016). Extracellular matrix stiffness dictates Wnt expression through integrin pathway. <em>Sci Rep, 6</em>, 20395. doi:10.1038/srep20395</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Foulquier, S., Daskalopoulos, E. P., Lluri, G., Hermans, K. C. M., Deb, A., & Blankesteijn, W. M. (2018). WNT Signaling in Cardiac and Vascular Disease. <em>Pharmacol Rev, 70</em>(1), 68-141. doi:10.1124/pr.117.013896</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Hua, Y., Yang, Y., Li, Q., He, X., Zhu, W., Wang, J., & Gan, X. (2018). Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/beta-catenin pathway. <em>J Biol Chem, 293</em>(51), 19710-19724. doi:10.1074/jbc.RA118.004434</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Jiang, X., Charlat, O., Zamponi, R., Yang, Y., & Cong, F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. <em>Mol Cell, 58</em>(3), 522-533. doi:10.1016/j.molcel.2015.03.015</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Katoh, M. (2001). Molecular cloning and characterization of human WNT3. <em>International journal of oncology, 19</em>(5), 977-982. Retrieved from <a href="https://www.ncbi.nlm.nih.gov/pubmed/11604997">https://www.ncbi.nlm.nih.gov/pubmed/11604997</a></span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Kusserow, A., Pang, K., Sturm, C., Hrouda, M., Lentfer, J., Schmidt, H. A., . . . Holstein, T. W. (2005). Unexpected complexity of the Wnt gene family in a sea anemone. <em>Nature, 433</em>(7022), 156-160. doi:10.1038/nature03158</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Lai, S. L., Chien, A. J., & Moon, R. T. (2009). Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. <em>Cell Res, 19</em>(5), 532-545. doi:10.1038/cr.2009.41</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. <em>Dev Cell, 17</em>(1), 9-26. doi:10.1016/j.devcel.2009.06.016</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Mohammed, M. K., Shao, C., Wang, J., Wei, Q., Wang, X., Collier, Z., . . . Lee, M. J. (2016). Wnt/beta-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. <em>Genes Dis, 3</em>(1), 11-40. doi:10.1016/j.gendis.2015.12.004</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Nile, A. H., Mukund, S., Stanger, K., Wang, W., & Hannoush, R. N. (2017). Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. <em>Proc Natl Acad Sci U S A, 114</em>(16), 4147-4152. doi:10.1073/pnas.1618293114</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. <em>Nature Communications, 7</em>(1), 13096. doi:10.1038/ncomms13096</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Saito-Diaz, K., Chen, T. W., Wang, X., Thorne, C. A., Wallace, H. A., Page-McCaw, A., & Lee, E. (2013). The way Wnt works: components and mechanism. <em>Growth Factors, 31</em>(1), 1-31. doi:10.3109/08977194.2012.752737</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Wang, B., Tang, Z., Gong, H., Zhu, L., & Liu, X. (2017). Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. <em>Biosci Rep, 37</em>(6). doi:10.1042/BSR20171092</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Willert, K., & Nusse, R. (2012). Wnt proteins. <em>Cold Spring Harb Perspect Biol, 4</em>(9), a007864. doi:10.1101/cshperspect.a007864</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Zeng, H., Lu, B., Zamponi, R., Yang, Z., Wetzel, K., Loureiro, J., . . . Cong, F. (2018). mTORC1 signaling suppresses Wnt/beta-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level. <em>Proc Natl Acad Sci U S A, 115</em>(44), E10362-E10369. doi:10.1073/pnas.1808575115</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. <em>PLoS One, 11</em>(8), e0160414. doi:10.1371/journal.pone.0160414</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Ziv, E., Yarmohammadi, H., Boas, F. E., Petre, E. N., Brown, K. T., Solomon, S. B., . . . Erinjeri, J. P. (2017). Gene Signature Associated with Upregulation of the Wnt/beta-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization. <em>J Vasc Interv Radiol, 28</em>(3), 349-355 e341. doi:10.1016/j.jvir.2016.11.004</span></span></p>
<h4><a href="/events/1755">Event: 1755: beta-catenin activation</a></h4>
<h5>Short Name: beta-catenin activation</h5>
<h4>Key Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>regulation of beta-catenin-TCF complex assembly</td>
<td>beta-catenin-TCF complex</td>
<td>occurrence</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/298">Aop:298 - Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<p>Beta-catenin is stabilized and translocated into nucleus in <em>Homo sapiens</em> (Huang et al., 2019).</p>
<p>Beta-catenin is activated in <em>Homo sapiens</em> (Huang et al., 2019) (Naujok et al., 2014). </p>
<h4>Key Event Description</h4>
<h3><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px">Upon the Wnt signaling activation, beta-catenin is stabilized and activated via inhibition of the phosphorylation by GSK3beta <!--[if supportFields]><span
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EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Huang et al., 2019)<!--[if gte mso 9]><xml>
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mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. Once the beta-catenin is stabilized, it translocates into the nucleus and enhances the expression of target genes of Wnt/beta-catenin signaling pathway <!--[if supportFields]><span
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Huang et al., 2019)<!--[if gte mso 9]><xml>
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</xml><![endif]--><!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
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mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. Beta-catenin activation is related to cancer <!--[if supportFields]><span lang=EN-US
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mso-bidi-font-family:"ＭＳＰゴシック";mso-font-kerning:0pt;mso-ansi-language:EN-US;
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ADDIN EN.CITE
<EndNote><Cite><Author>Tanabe</Author><Year>2014</Year><RecNum>134</RecNum><DisplayText>(Tanabe,
2014)</DisplayText><record><rec-number>134</rec-number><foreign-keys><key
app="EN" db-id="zfxrap00xevas9efewrvfezhzrxpw2a9zw50" timestamp="1570495671">134</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Tanabe,
Shihori</author></authors></contributors><titles><title>Role
of mesenchymal stem cells in cell life and their signaling</title><secondary-title>World
journal of stem cells</secondary-title><alt-title>World J Stem
Cells</alt-title></titles><alt-periodical><full-title>World
J Stem Cells</full-title></alt-periodical><pages>24-32</pages><volume>6</volume><number>1</number><edition>2014/01/26</edition><keywords><keyword>Application</keyword><keyword>Differentiation</keyword><keyword>Mesenchymal
stem
cell</keyword><keyword>Self-renewal</keyword><keyword>Stem
cell</keyword></keywords><dates><year>2014</year></dates><publisher>Baishideng
Publishing Group Co.,
Limited</publisher><isbn>1948-0210</isbn><accession-num>24567785</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/24567785</url><url>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927011/</url></related-urls></urls><electronic-resource-num>10.4252/wjsc.v6.i1.24</electronic-resource-num><remote-database-name>PubMed</remote-database-name><language>eng</language></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(Tanabe, 2014)<!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:"ＭＳＰゴシック";mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-end'></span></span><![endif]-->.</span></span></h3>
<h3><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px"><span style="background-color:#ffffff; color:#333333">Dishevelled (DVL), a positive regulator of Wnt signaling, forms the complex with FZD and leads to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (</span><a href="https://aopwiki.org/events/1754#_ENREF_14" style="background-color: transparent; box-sizing: border-box; color: rgb(51, 122, 183); font-family: &quot;helvetica neue&quot;,helvetica,arial,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; -webkit-text-stroke-width: 0px; white-space: normal; word-spacing: 0px;" title="Clevers, 2012 #10">Clevers & Nusse, 2012</a><span style="background-color:#ffffff; color:#333333">; </span><a href="https://aopwiki.org/events/1754#_ENREF_36" style="background-color: transparent; box-sizing: border-box; color: rgb(51, 122, 183); font-family: &quot;helvetica neue&quot;,helvetica,arial,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; -webkit-text-stroke-width: 0px; white-space: normal; word-spacing: 0px;" title="Jiang, 2015 #95">Jiang, et al., 2015</a><span style="background-color:#ffffff; color:#333333">). DVL, however, has a controversial role to promote Wnt receptor degradation </span><span style="background-color:#ffffff; color:#333333">(</span><a href="https://aopwiki.org/events/1754#_ENREF_36" style="background-color: transparent; box-sizing: border-box; color: rgb(51, 122, 183); font-family: &quot;helvetica neue&quot;,helvetica,arial,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; -webkit-text-stroke-width: 0px; white-space: normal; word-spacing: 0px;" title="Jiang, 2015 #95">Jiang et al., 2015</a><span style="background-color:#ffffff; color:#333333">). Meanwhile, DVL-dependent regulation of FZD level is involved in mTORC1 signaling suppression via Wnt/beta-catenin signaling </span><span style="background-color:#ffffff; color:#333333">(</span><a href="https://aopwiki.org/events/1754#_ENREF_113" style="background-color: transparent; box-sizing: border-box; color: rgb(51, 122, 183); font-family: &quot;helvetica neue&quot;,helvetica,arial,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; -webkit-text-stroke-width: 0px; white-space: normal; word-spacing: 0px;" title="Zeng, 2018 #94">Zeng et al., 2018</a><span style="background-color:#ffffff; color:#333333">). The recruitment of Axin to the DVL-FZD complex induces the beta-catenin stabilization and activation. The stabilized beta-catenin translocates into the nucleus, which forms the complex with TCF to induce the up-regulated expression of proliferation-related genes.</span></span></span></h3>
<h4>How it is Measured or Detected</h4>
<p>The beta-catenin level in nucleus is measured by immunoblotting with anti-beta-catenin antibody (Huang et al., 2019).</p>
<p></p>
<p>The beta-catenin nuclear translocation is measured by immunofluorescence assay (Huang et al., 2019).</p>
<p>Activity of beta-catenin is measured by Wnt/beta-catenin activity assay, in which the vector containing the firefly luciferase gene controlled by TCF/LEF binding sites is transfected in the cells (Naujok et al., 2014). </p>
<h4>References</h4>
<p style="margin-left:36.0pt"><span style="font-size:14px"><span style="font-family:arial,helvetica,sans-serif"><span style="background-color:#ffffff; color:#333333">Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. </span><em>Cell, 149</em><span style="background-color:#ffffff; color:#333333">(6), 1192-1205. doi:10.1016/j.cell.2012.05.012</span></span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:14px"><span style="font-family:arial,helvetica,sans-serif"><span style="background-color:#ffffff; color:#333333">Huang, J. Q., Wei, F. K., Xu, X. L., Ye, S. X., Song, J. W., Ding, P. K., . . . Gong, L. Y. (2019). SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/beta-catenin pathway. </span><em>J Transl Med, 17</em><span style="background-color:#ffffff; color:#333333">(1), 143. doi:10.1186/s12967-019-1895-2</span></span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:14px"><span style="font-family:arial,helvetica,sans-serif"><span style="background-color:#ffffff; color:#333333">Jiang, X., Charlat, O., Zamponi, R., Yang, Y., & Cong, F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. </span><em>Mol Cell, 58</em><span style="background-color:#ffffff; color:#333333">(3), 522-533. doi:10.1016/j.molcel.2015.03.015</span></span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:14px"><span style="font-family:arial,helvetica,sans-serif">Naujok, O., Lentes, J., Diekmann, U., Davenport, C., & Lenzen, S. (2014). Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. <em>BMC Res Notes, 7</em>, 273. doi:10.1186/1756-0500-7-273</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:14px"><span style="font-family:arial,helvetica,sans-serif">Tanabe, S. (2014). Role of mesenchymal stem cells in cell life and their signaling. <em>World journal of stem cells, 6</em>(1), 24-32. doi:10.4252/wjsc.v6.i1.24</span></span></p>
<p style="margin-left:36.0pt"><span style="font-size:14px"><span style="font-family:arial,helvetica,sans-serif"><span style="background-color:#ffffff; color:#333333">Zeng, H., Lu, B., Zamponi, R., Yang, Z., Wetzel, K., Loureiro, J., . . . Cong, F. (2018). mTORC1 signaling suppresses Wnt/beta-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level. </span><em>Proc Natl Acad Sci U S A, 115</em><span style="background-color:#ffffff; color:#333333">(44), E10362-E10369. doi:10.1073/pnas.1808575115</span></span></span></p>
<h4><a href="/events/1457">Event: 1457: Epithelial Mesenchymal Transition</a></h4>
<h5>Short Name: EMT</h5>
<h4>Key Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>epithelial to mesenchymal transition</td>
<td>Epithelial cell</td>
<td>occurrence</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/241">Aop:241 - Latent Transforming Growth Factor beta1 activation leads to pulmonary fibrosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/206">Aop:206 - Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/280">Aop:280 - α-diketone-induced bronchiolitis obliterans</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/347">Aop:347 - Toll-like receptor 4 activation and peroxisome proliferator-activated receptor gamma inactivation leading to pulmonary fibrosis</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/414">Aop:414 - Aryl hydrocarbon receptor activation leading to lung fibrosis through TGF-β dependent fibrosis toxicity pathway</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/415">Aop:415 - Aryl hydrocarbon receptor activation leading to lung fibrosis through IL-6 toxicity pathway</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/443">Aop:443 - DNA damage and mutations leading to Metastatic Breast Cancer</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/298">Aop:298 - Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/452">Aop:452 - Adverse outcome pathway of PM-induced respiratory toxicity</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/474">Aop:474 - Succinate dehydrogenase inactivation leads to cancer by promoting EMT</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>epithelial cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>humans</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Not Otherwise Specified</td>
<td>Not Specified</td>
</tr>
</tbody>
</table>
</div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>Not Specified</td>
</tr>
</tbody>
</table>
</div>
<p style="text-align:left">The key event is applicaple in <em>Homo sapiens</em>:</p>
<ul>
<li style="text-align:left"><span style="font-size:10.5pt"><span style="color:black"><span style="font-family:游明朝,serif"><span style="font-size:12pt"><span style="font-family:"ＭＳＰゴシック",sans-serif">Wnt5a expression leads to epithelial-mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer in <em>Homo sapiens</em> (Wang et al., 2017).</span></span></span></span></span></li>
<li style="text-align:left"><span style="font-size:10.5pt"><span style="color:black"><span style="font-family:游明朝,serif"><span style="font-size:12pt"><span style="font-family:"ＭＳＰゴシック",sans-serif">WNT2 expression lead to EMT induction in <em>Homo sapiens</em> (Zhou et al., 2016).</span></span></span></span></span></li>
<li style="text-align:left"><span style="font-size:10.5pt"><span style="color:black"><span style="font-family:游明朝,serif"><span style="font-size:12pt"><span style="font-family:"ＭＳＰゴシック",sans-serif">EMT is induced in cancer and involved in cancer metastasis in <em>Homo sapiens</em> (Suarez-Carmona, Lesage, Cataldo, & Gilles, 2017) (Du & Shim, 2016).</span></span></span></span></span></li>
</ul>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Regulation of miRNA expression by DNA replication,damage and repair responses,transcription and translation has been proved in animals like mice,canine and cell line experiments.</span></span></p>
<h4>Key Event Description</h4>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">Epithelial-mesenchymal transition (EMT) is a phenomenon in which the cells transit from epithelial-like into mesenchymal-like phenotypes (Huan et al., 2022; Tanabe, 2017; Tanabe et al., 2015). In cancer, cells exhibiting EMT features contribute to metastasis and drug resistance.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">It is known that D-2-hydroxyglurate induces EMT (Guerra et al., 2017; Jia et al., 2018; Mishra et al., 2018; Sciacovelli & Frezza, 2017). D-2-hydroxyglurate, an inhibitor of Jumonji-family histone demethylase, increased the trimethylation of histone H3 lysine 4 (H3K4) in the promoter region of the zinc finger E-box-binding homeobox 1 (ZEB1), followed by the induction of EMT (Colvin et al., 2016).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">Wnt5a induces EMT and metastasis in non-small-cell lung cancer (Wang et al., 2017).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">EMT is related to Wnt/beta-catenin signaling and is important for treatment-resistant cancer (Tanabe et al., 2016).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">TGFbeta induces EMT (Wendt et al., 2010).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">ZEB is one of the critical transcription factors for EMT regulation (Zhang et al., 2015).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">SNAI1 (Snail) is an important transcription factor for cell differentiation and survival. The phosphorylation and nuclear localization of Snail1 induced by Wnt signaling pathways are critical for the regulation of EMT (Kaufhold & Bonavida, 2014).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">Transcription factors SNAI1 and TWIST1 induce EMT (Hodge et al., 2018) (Mani et al., 2008).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:"ＭＳＰゴシック",sans-serif"><span style="color:#000000"><span style="color:black">It is suggested that Sp1, a transcription factor involved in cell growth and metastasis, is induced by cytochrome P450 1B1 (CYP1B1), and promotes EMT, which leads to cell proliferation and metastasis (Kwon et al., 2016).</span></span></span></span></p>
<table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:601px">
<tbody>
<tr>
<td style="background-color:#eaf1dd; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:601px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological state</span></strong></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An epithelial-mesenchymal transition (EMT) is a biologic process in which epithelial cells are polarized, interact through their basal surface with basement membrane, and undergo biochemical changes to assume a mesenchymal cell phenotype. </span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">This phenotypic transformation has various characters such as enhanced migratory capacity, high invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components (Kalluri,  R.,  and  Neilson,  E.G.  2003). The completion of an EMT is signalled by the degradation of the underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.</span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> EMT has a number of distinct molecular processes like activation of transcription factors, expression of specific cell surface proteins, reorganization and expression of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in the expression of specific microRNAs. These factors are used as biomarkers to demonstrate the passage of a  cell through an EMT. </span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological compartment </span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Cellular</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Role in General Biology:</span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Excessive proliferation of epithelial cells and angiogenesis mark the initiation and early growth of primary epithelial cancers. (Hanahan, D., and Weinberg, R.A. 2000). The subsequent acquisition of invasiveness, initially manifest by invasion through the basement membrane, is thought  to herald the onset of the last stages of the multi-step process that  leads eventually to metastatic dissemination, with life-threatening  consequences.  There has been an intense research going on in the genetic controls and biochemical mechanisms underlying the acquisition of the invasive phenotype and the subsequent systemic spread of the cancer cell.  Activation of an EMT program has been proposed as the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells (Thiery, J.P. 2002).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> Pre-clinical experiments such as mice models and cell culture experiments  has demonstrated  that carcinoma cells can acquire a mesenchymal phenotype and express mesenchymal markers such as </span><span style="color:black">α</span><span style="color:black">-SMA, FSP1, vimentin,  and desmin (Yang,  J.,  and  Weinberg,  R.A.  2008). These cells  are seen at the invasive front  of primary tumors and are considered to be the cells that eventually  enter into subsequent steps of the invasion-metastasis cascade, i.e.,  intravasation, transport through the circulation, extravasation, formation of micro metastases, and ultimately colonization (the growth  of small colonies into macroscopic metastases) (Thiery, J.P. 2002, Fidler, I.J., and Poste, G. 2008, Brabletz, T., et al. 2001).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An  apparent  paradox  comes  from  the  observation  that  the  EMT-derived migratory cancer cells typically establish secondary colonies at distant sites that resemble, at the histopathological  level, the primary tumor from which they arose; accordingly,  they no longer exhibit the mesenchymal phenotypes ascribed to  metastasizing  carcinoma  cells.  Reconciling this behaviour with the proposed role of EMT as a facilitator of metastatic dissemination requires the additional notion that metastasizing cancer cells must shed their mesenchymal phenotype via a MET during  the course of secondary tumor formation (Zeisberg, M et al 2005). The tendency of  disseminated cancer cells to undergo EMT likely reflects the local  microenvironments that they encounter after extravasation into  the parenchyma of a distant organ, quite possibly the absence of  the heterotypic signals they experienced in the primary tumor that  were responsible for inducing the EMT in the first place (Thiery, J.P. 2002, Jechlinger, M et al 2002, Bissell, M.J et al 2002). These evidences indicate that induction of an EMT is likely to be a centrally important mechanism for the progression of carcinomas to a metastatic stage and implicates MET during the subsequent colonization process. However, many steps of this mechanistic model still require direct experimental validation. It remains unclear at present whether these phenomena and molecular mechanisms relate to and explain the metastatic dissemination of non-epithelial cancer cells.</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">The entire spectrum of signaling agents that contribute to EMTs of carcinoma cells remains unclear. One  theory suggests that  the genetic and epigenetic alterations undergone by cancer cells during the course of primary tumor formation render them especially responsive to EMT-inducing heterotypic signals originating in the tumor-associated stroma. Oncogenes induce senescence, and recent studies suggest that cancer cell EMTs may also play a role in preventing senescence induced by oncogenes, thereby facilitating subsequent aggressive dissemination (Smit, M.A., and Peeper, D.S. 2008, Ansieau, S., et al. 2008, Weinberg, R.A. 2008).  In  the case of many carcinomas, EMT-inducing signals emanating  from the tumor-associated stroma, notably HGF, EGF, PDGF,  and TGF-</span><span style="color:black">β</span><span style="color:black">, appear to be responsible for the induction or functional  activation  in  cancer  cells  of  a  series  of  EMT-inducing  transcription factors, notably Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), Twist, Goosecoid, and FOXC2 (Thiery, J.P. 2002, Jechlinger, M  et al 2002, Shi, Y., and Massague, J. 2003, Niessen, K., et al. 2008, Medici, D et al 2008, Kokudo,  T.,  et  al.  2008). Once expressed and activated, each of these transcription factors can act pleiotropically to choreograph the complex EMT program, more often than not with the help of other members of this cohort of transcription factors. The actual implementation by these cells of their EMT program depends on a series of  intracellular signaling networks involving, among other signal- transducing  proteins,  ERK,  MAPK,  PI3K,  Akt,  Smads,  RhoB,  </span><span style="color:black">β</span><span style="color:black">-catenin, lymphoid enhancer binding factor (LEF), Ras, and c-Fos  as well as cell surface proteins such as </span><span style="color:black">β</span><span style="color:black">4 integrins, </span><span style="color:black">α</span><span style="color:black">5</span><span style="color:black">β</span><span style="color:black">1 integrin, and </span><span style="color:black">α</span><span style="color:black">V</span><span style="color:black">β</span><span style="color:black">6 integrin (Tse,  J.C.,  and  Kalluri,  R.  2007). Activation of EMT programs is also facilitated by the disruption of cell-cell adherens junctions and the cell-ECM adhesions mediated by integrins (Yang,  J.,  and  Weinberg,  R.A.  2008, Weinberg, R.A. 2008, Gupta, P.B  et al 2005, Yang,  J et al 2006, Mani, S.A., et al. 2007, Mani, S.A., et al. 2008, Hartwell, K.A., et al. 2006, Taki, M et al 2006)..</span></span></span></p>
<p> </p>
</td>
</tr>
</tbody>
</table>
<h4>How it is Measured or Detected</h4>
<p>Loss of <a href="https://en.wikipedia.org/wiki/E-cadherin">E-cadherin</a> and cell polarity is considered to be a fundamental event in epithelial-mesenchymal transition. The simultaneous expression of epithelial (e.g. E-cadherin) and mesenchymal markers (e.g. N-cadherin and vimentin) within the airway epithelium are indicative for ongoing transition (Borthwick et al. 2009, 2010).</p>
<table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:586px">
<tbody>
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<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:58px">
<p style="text-align:justify"> </p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Method/ measurement referenc</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:73px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Reliability</span></span></p>
<p style="text-align:justify"> </p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strength of evidence</span></span></p>
<p style="text-align:justify"> </p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Assay fit for purpose</span></span></p>
<p style="text-align:justify"> </p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Repeatability/ reproducibility</span></span></p>
<p style="text-align:justify"> </p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Direct measure</span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human cell line</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">qRT-PCR,cell viability assay,</span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Western blotting,EdU incorporation assay</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strong</span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">IHC,micro array,qPCR, SNP array</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Moderate</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
</tr>
</tbody>
</table>
<ul>
<li style="text-align:left"><span style="font-size:10.5pt"><span style="color:black"><span style="font-family:游明朝,serif"><span style="font-size:12pt"><span style="font-family:"ＭＳＰゴシック",sans-serif">EMT can be detected by immunostaining with pro-surfactant protein-C (pro-SPC) and N-cadherin in idiopathic pulmonary fibrosis (IPF) lung <em>in vivo</em> (Kim et al., 2006).</span></span></span></span></span></li>
<li style="text-align:left"><span style="font-size:10.5pt"><span style="color:black"><span style="font-family:游明朝,serif"><span style="font-size:12pt"><span style="font-family:"ＭＳＰゴシック",sans-serif">EMT can be detected by immunostaining with vimentin in lung alveola <em>in vivo</em> (Kim et al., 2006).</span></span></span></span></span></li>
<li style="text-align:left"><span style="font-size:10.5pt"><span style="color:black"><span style="font-family:游明朝,serif"><span style="font-size:12pt"><span style="font-family:"ＭＳＰゴシック",sans-serif">EMT can be detected as the increased level of the transcription factors, zinc finger E-box-binding homeobox (ZEB), Twist and Snail (Huang et al., 2022).</span></span></span></span></span></li>
</ul>
<p> </p>
<h4>References</h4>
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<p>Borthwick, L. A., McIlroy, E. I., Gorowiec, M. R., Brodlie, M., Johnson, G. E., Ward, C., … Fisher, A. J. (2010). Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Role in dysregulated epithelial wound repair. <em>American Journal of Transplantation</em>, <em>10</em>(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x"><u>https://doi.org/10.1111/j.1600-6143.2009.02953.x</u></a></p>
<p>Al Saleh, S., Al Mulla, F., & Luqmani, Y. A. (2011). Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PloS one, 6(6), e20610.</p>
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<p>Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S., & Moro, L. (2017). Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer. <em>Front Oncol, 7</em>, 295. doi:10.3389/fonc.2017.00295</p>
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<p>Tse, J. C., & Kalluri, R. (2007). Mechanisms of metastasis: epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment. Journal of cellular biochemistry, 101(4), 816-829.</p>
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<p>Yang, J., & Weinberg, R. A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental cell, 14(6), 818-829.</p>
<p>Yang, J., Mani, S. A., & Weinberg, R. A. (2006). Exploring a new twist on tumor metastasis. Cancer research, 66(9), 4549-4552.</p>
<p>Ye, Y., Xiao, Y., Wang, W., Yearsley, K., Gao, J. X., Shetuni, B., & Barsky, S. H. (2010). ERα signaling through slug regulates E-cadherin and EMT. Oncogene, 29(10), 1451-1462.</p>
<p>Zeisberg, M., Shah, A. A., & Kalluri, R. (2005). Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. Journal of Biological Chemistry, 280(9), 8094-8100.</p>
<p>Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. Journal of proteomics, 103, 153-169.</p>
<p>Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. <em>Cell Cycle, 14</em>(4), 481-487. doi:10.1080/15384101.2015.1006048</p>
<p>Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. <em>PLoS One, 11</em>(8), e0160414. doi:10.1371/journal.pone.0160414</p>
<h3>List of Adverse Outcomes in this AOP</h3>
<h4><a href="/events/1651">Event: 1651: Treatment-resistant gastric cancer</a></h4>
<h5>Short Name: Resistant gastric cancer</h5>
<h4>Key Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>regulation of cellular response to drug</td>
<td></td>
<td>occurrence</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/298">Aop:298 - Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>AdverseOutcome</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Tissue</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">Drug resistance occurs in <em>Homo sapiens</em> <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Du</Author><Year>2016</Year><RecNum>57</RecNum><DisplayText>(Du
&amp; Shim,
2016)</DisplayText><record><rec-number>57</rec-number><foreign-keys><key
app="EN" db-id="z0t2vdzwlt05d9ewr09vwwd85sdd5wtsarsd"
timestamp="1584950464">57</key></foreign-keys><ref-type
name="Journal Article">17</ref-type><contributors><authors><author>Du,
B.</author><author>Shim, J.
S.</author></authors></contributors><auth-address>Faculty
of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau
SAR 999078, China. dbw@mail.ustc.edu.cn.&#xD;Faculty of Health Sciences,
University of Macau, Avenida da Universidade, Taipa, Macau SAR 999078, China.
jsshim@umac.mo.</auth-address><titles><title>Targeting
Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in
Cancer</title><secondary-title>Molecules</secondary-title></titles><volume>21</volume><number>7</number><edition>2016/07/28</edition><keywords><keyword>Animals</keyword><keyword>Antineoplastic
Agents/*pharmacology/therapeutic use</keyword><keyword>Drug
Discovery</keyword><keyword>Drug Resistance, Neoplasm/*drug
effects/genetics</keyword><keyword>Epithelial-Mesenchymal
Transition/*drug
effects/genetics</keyword><keyword>Humans</keyword><keyword>Neoplasms/drug
therapy/etiology/metabolism/pathology</keyword><keyword>Neoplastic
Stem Cells/drug effects/metabolism</keyword><keyword>Signal
Transduction/drug effects</keyword><keyword>Tumor
Microenvironment</keyword><keyword>cancer stem
cells</keyword><keyword>chemotherapy</keyword><keyword>drug
resistance</keyword><keyword>epithelial-mesenchymal transition</keyword></keywords><dates><year>2016</year><pub-dates><date>Jul
22</date></pub-dates></dates><isbn>1420-3049
(Electronic)&#xD;1420-3049 (Linking)</isbn><accession-num>27455225</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/27455225</url></related-urls></urls><custom2>PMC6273543</custom2><electronic-resource-num>10.3390/molecules21070965</electronic-resource-num></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(Du & Shim, 2016)<!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-end'></span></span><![endif]-->.</span></span></p>
<h4>Key Event Description</h4>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">It is known that diffuse-type gastric cancer, which has a poor prognosis, is treatment-resistant and more malignant compared to intestinal-type gastric cancer (Tanabe et al., 2014). Drug resistance is involved in EMT, which is an important phenomenon exhibiting features similar to cancer stem cells (CSCs) (Du & Shim, 2016).</span></span></p>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">EMT is involved in metastasis and cancer therapy resistance (Smith & Bhowmick, 2016).</span></span><br />
</p>
<h4>How it is Measured or Detected</h4>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">Treatment-resistant gastric cancer and EMT can be detected with biomarkers (Zeisberg & Neilson, 2009).</span></span></p>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">Treatment-resistant gastric cancer which exhibits EMT phenotype can be detected as the increased level of the transcription factors, zinc finger E-box-binding homeobox 1/2 (ZEB1/2), SNAI1/2, and TWIST2 which are associated with the activation of EMT-related genes (Tanabe et al., 2022a and 2022b).</span></span></p>
<h4>Regulatory Significance of the AO</h4>
<p><span style="font-size:18px"><span style="font-family:Arial,Helvetica,sans-serif">Drug resistance is very important in cancer treatment since cancer metastasis and recurrence are some of the main obstacles to treating cancer. Cancer stem cells that share the phenotype of EMT may be targeted in anti-cancer drug development. </span></span></p>
<h4>References</h4>
<p style="margin-left:36.0pt"><!--[if supportFields]><span
lang=EN-US><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.REFLIST <span style='mso-element:
field-separator'></span></span><![endif]--><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. <em>Molecules, 21</em>(7). doi:10.3390/molecules21070965</span></span></p>
<p style="margin-left:36.0pt"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in Metastasis and Therapy Resistance. <em>J Clin Med, 5</em>(2). doi:10.3390/jcm5020017</span></span></p>
<p style="margin-left:36.0pt"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Tanabe, S., Aoyagi, K., Yokozaki, H., Sasaki, H. (2014). Gene expression signatures for identifying diffuse-type gastric cancer associated with epithelial-mesenchymal transition. <em>International journal of oncology, 44</em>(6), 1955-1970. doi:10.3892/ijo.2014.2387</span></span></p>
<p style="margin-left:36.0pt"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Tanabe, S., Quader, S., Cabral, H., Ono, R. (2020a). Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies. <em>Front Pharmacol,</em> <em>11</em>, 904. doi:<a href="https://doi.org/10.3389/fphar.2020.00904">10.3389/fphar.2020.00904</a></span></span></p>
<p style="margin-left:36.0pt"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Tanabe S, Quader S, Ono R, Cabral H, Aoyagi K, Hirose A, Yokozaki H., Sasaki, H. (2020b). Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer. <em>Cancers (Basel),</em> <em>12</em>(12), 3833. doi:<a href="https://doi.org/10.3390/cancers12123833">10.3390/cancers12123833</a></span></span></p>
<p style="margin-left:36.0pt"><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:18px">Zeisberg, M., & Neilson, E. G. (2009). Biomarkers for epithelial-mesenchymal transitions. <em>J Clin Invest, 119</em>(6), 1429-1437. doi:10.1172/JCI36183</span></span></p>
<p><!--[if supportFields]><span lang=EN-US style='font-size:12.0pt;font-family:
"ＭＳＰゴシック",sans-serif;mso-bidi-font-family:"ＭＳＰゴシック";mso-font-kerning:0pt;
mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span
style='mso-element:field-end'></span></span><![endif]--></p>
<h2>Appendix 2</h2>
<h2>List of Key Event Relationships in the AOP</h2>
<div id="evidence_supporting_links">
<h3>List of Adjacent Key Event Relationships</h3>
<div>
<h4><a href="/relationships/3505">Relationship: 3505: Increase, ROS leads to Increase, porcupine-induced Wnt secretion and Wnt signaling activation</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/298">Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>adjacent</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<p>Prolonged ROS induces inflammation and tissue damage in <em>Homo sapiens</em> (Vallée & Lecarpentier, 2018). </p>
</div>
<h4>Key Event Relationship Description</h4>
<p><span style="font-size:18px">ROS production causes tissue damage (Gao, Zhou, Lin, Paus, & Yue, 2019). ROS production is involved in Wnt-driven tumorigenesis (Myant et al., 2013). The prolonged ROS induces inflammation leading to carcinogenesis (Vallée & Lecarpentier,2018). Injury causes the Porcupine-induced Wnt secretion (Saha et al., 2016).</span></p>
<h4>Evidence Supporting this KER</h4>
<strong>Biological Plausibility</strong>
<p>Sustained ROS increase caused by/causes DNA damage, which will alter several signaling pathways including Wnt signaling.</p>
<p>Macrophages accumulate into injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion. ROS stimulate inflammatory factor production and Wnt/beta-catenin signaling (Vallée & Lecarpentier, 2018).</p>
<strong>Empirical Evidence</strong>
<div>
<p>Production of ROS by DNA double-strand break causes tissue damages (Gao et al., 2019).</p>
<p>ROS signaling induces Wnt/beta-catenin signaling (Pérez, Taléns-Visconti, Rius-Pérez, Finamor, & Sastre, 2017).</p>
</div>
<strong>Uncertainties and Inconsistencies</strong>
<div>
<p>The balance of ROS signaling is important, and dual effects of ROS should be taken in consideration. The ROS may enhance Wnt/beta-catenin proliferating pathways to promote tumorigenesis, while ROS may disrupt tumor progression by different pro-apoptotic mechanisms (Pérez et al., 2017). It is also known that Wnt signaling induces ROS signaling (Cheung et al., 2016). Wnt/beta-catenin signaling control by ROS needs to be further investigated (Caliceti, Nigro, Rizzo, & Ferrari, 2014).</p>
</div>
<h4>Quantitative Understanding of the Linkage</h4>
<strong>Response-response relationship</strong>
<div>
<p>ROS induces inflammatory responses (Bhattacharyya, Chattopadhyay, Mitra, & Crowe, 2014). Oxidant induces ROS generation and p38 MAPK activation in macrophages (Conway & Kinter, 2006). ROS induce tissue damage in cardiac myocytes (Miller & Cheung, 2016; Yang et al., 2006).</p>
</div>
<strong>Time-scale</strong>
<div>
<p>For the colony formation assay, cells were treated with 400 microM/L H2O2 for 1 week, where the medium was changed every three days (Wang et al., 2019).</p>
</div>
<strong>Known modulating factors</strong>
<div>
<p>GPX2, an activator of Wnt/beta-catenin signaling, is identified as a key regulator of intracellular H2O2 levels and an inhibitor of apoptosis (Wang et al., 2019).</p>
</div>
<strong>Known Feedforward/Feedback loops influencing this KER</strong>
<div>
<p>The reduction in ROS levels in the human serum albumin-treated cerebral ischemia/reperfusion-induced injury may be mediated by Wnt/betacatenin signaling (Tang, Shen, Zhang, Yang, & Liu, 2019).</p>
</div>
<h4>References</h4>
<div>
<p>Bhattacharyya, A., Chattopadhyay, R., Mitra, S., & Crowe, S. E. (2014). Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiological reviews, 94(2), 329-354. doi:10.1152/physrev.00040.2012</p>
<p>Caliceti, C., Nigro, P., Rizzo, P., & Ferrari, R. (2014). ROS, Notch, and Wnt signaling pathways: crosstalk between three major regulators of cardiovascular biology. BioMed research international, 2014, 318714-318714. doi:10.1155/2014/318714</p>
<p>Cheung, E. C., Lee, P., Ceteci, F., Nixon, C., Blyth, K., Sansom, O. J., & Vousden, K. H. (2016). Opposing effects of TIGAR- and RAC1-derived ROS on Wnt driven proliferation in the mouse intestine. Genes & development, 30(1), 52-63. doi:10.1101/gad.271130.115</p>
<p>Conway, J. P., & Kinter, M. (2006). Dual role of peroxiredoxin I in macrophage-derived foam cells. The Journal of biological chemistry, 281(38), 27991-28001. doi:10.1074/jbc.M605026200</p>
<p>Gao, Q., Zhou, G., Lin, S.-J., Paus, R., & Yue, Z. (2019). How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models. Experimental dermatology, 28(4), 413-418. doi:10.1111/exd.13846</p>
<p>Miller, B. A., & Cheung, J. Y. (2016). TRPM2 protects against tissue damage following oxidative stress and ischaemia-reperfusion. The Journal of physiology, 594(15), 4181-4191. doi:10.1113/JP270934</p>
<p>Myant, K. B., Cammareri, P., McGhee, E. J., Ridgway, R. A., Huels, D. J., Cordero, J. B., . . . Sansom, O. J. (2013). ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell stem cell, 12(6), 761-773. doi:10.1016/j.stem.2013.04.006</p>
<p>Pérez, S., Taléns-Visconti, R., Rius-Pérez, S., Finamor, I., & Sastre, J. (2017). Redox signaling in the gastrointestinal tract. Free radical biology & medicine, 104, 75-103. doi:10.1016/j.freeradbiomed.2016.12.048</p>
<p>Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nature Communications, 7, 13096-13096. doi:10.1038/ncomms13096</p>
<p>Tang, Y., Shen, J., Zhang, F., Yang, F.-Y., & Liu, M. (2019). Human serum albumin attenuates global cerebral ischemia/reperfusion-induced brain injury in a Wnt/β- Catenin/ROS signaling-dependent manner in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 115, 108871-108871. doi:10.1016/j.biopha.2019.108871</p>
<p>Vallée, A., & Lecarpentier, Y. (2018). Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/β-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis. Frontiers in immunology, 9, 745-745. doi:10.3389/fimmu.2018.00745</p>
<p>Wang, Y., Cao, P., Alshwmi, M., Jiang, N., Xiao, Z., Jiang, F., . . . Li, S. (2019). GPX2 suppression of H(2)O(2) stress regulates cervical cancer metastasis and apoptosis via activation of the β-catenin-WNT pathway. OncoTargets and therapy, 12, 6639-6651. doi:10.2147/OTT.S208781</p>
<p>Yang, K. T., Chang, W. L., Yang, P. C., Chien, C. L., Lai, M. S., Su, M. J., & Wu, M. L. (2006). Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death. Cell Death & Differentiation, 13(10), 1815-1826. doi:10.1038/sj.cdd.4401813</p>
</div>
</div>
<div>
<h4><a href="/relationships/2070">Relationship: 2070: Increase, porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/298">Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>adjacent</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Wnt/beta-catenin signaling, which regulates key cellular functions including proliferation, is a highly conserved pathway through evolution (Pai et al., 2017).</span></span></p>
<h4>Key Event Relationship Description</h4>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Secreted Wnt ligand stimulates Wnt/beta-catenin signaling, in which beta-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3beta inactivation. GSK3beta inactivation leads to beta-catenin dephosphorylation, which avoids the ubiquitination of the beta-catenin and stabilizes the beta-catenin <!--[if supportFields]><span lang=EN-US style='font-size:
14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";mso-bidi-font-family:
Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;mso-fareast-language:JA;
mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Clevers</Author><Year>2012</Year><RecNum>10</RecNum><DisplayText>(Clevers
&amp; Nusse, 2012)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key
app="EN" db-id="z0t2vdzwlt05d9ewr09vwwd85sdd5wtsarsd" timestamp="1584950464">10</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Clevers,
H.</author><author>Nusse, R.</author></authors></contributors><auth-address>Hubrecht
Institute, KNAW and University Medical Center Utrecht, The Netherlands.
h.clevers@hubrecht.eu</auth-address><titles><title>Wnt/beta-catenin
signaling and
disease</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>1192-205</pages><volume>149</volume><number>6</number><edition>2012/06/12</edition><keywords><keyword>Animals</keyword><keyword>Disease/genetics</keyword><keyword>Humans</keyword><keyword>Wnt
Proteins/*metabolism</keyword><keyword>*Wnt Signaling
Pathway</keyword><keyword>beta Catenin/*metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun
8</date></pub-dates></dates><isbn>1097-4172
(Electronic)&#xD;0092-8674 (Linking)</isbn><accession-num>22682243</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/22682243</url></related-urls></urls><electronic-resource-num>10.1016/j.cell.2012.05.012</electronic-resource-num></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(Clevers & Nusse, 2012)<!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The translocation of stabilized beta-catenin induces the transcription of genes involved in proliferation (Pai et al., 2017).</span></span></p>
<h4>Evidence Supporting this KER</h4>
<strong>Biological Plausibility</strong>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Canonical Wnt pathway consists of Wnt, GSK3beta, and beta-catenin cascade (Clevers & Nusse, 2012; Hatsell, Rowlands, Hiremath, & Cowin, 2003).</span></span><span style="font-family:arial,helvetica,sans-serif"></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">GSK3beta recruitment to LRP6 leads to form un-phosphorylated beta-catenin inducing the stabilization and translocation of the beta-catenin (MacDonald, Tamai, & He, 2009). </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Stabilized beta-catenin accumulates in cytosol and translocates into the nucleus leading to beta-catenin activation <!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>MacDonald</Author><Year>2009</Year><RecNum>93</RecNum><DisplayText>(MacDonald
et al.,
2009)</DisplayText><record><rec-number>93</rec-number><foreign-keys><key
app="EN" db-id="z0t2vdzwlt05d9ewr09vwwd85sdd5wtsarsd"
timestamp="1584950464">93</key></foreign-keys><ref-type
name="Journal Article">17</ref-type><contributors><authors><author>MacDonald,
B. T.</author><author>Tamai, K.</author><author>He,
X.</author></authors></contributors><auth-address>F. M.
Kirby Neurobiology Center, Children&apos;s Hospital Boston, Harvard Medical
School, Boston, MA 02115,
USA.</auth-address><titles><title>Wnt/beta-catenin signaling:
components, mechanisms, and diseases</title><secondary-title>Dev
Cell</secondary-title></titles><pages>9-26</pages><volume>17</volume><number>1</number><edition>2009/07/22</edition><keywords><keyword>Active
Transport, Cell
Nucleus/physiology</keyword><keyword>Animals</keyword><keyword>Axin
Protein</keyword><keyword>*Disease</keyword><keyword>Frizzled
Receptors/metabolism</keyword><keyword>Humans</keyword><keyword>Ligands</keyword><keyword>Low
Density Lipoprotein Receptor-Related
Protein-6</keyword><keyword>Receptors,
LDL/metabolism</keyword><keyword>Repressor
Proteins/genetics/metabolism</keyword><keyword>Signal
Transduction/*physiology</keyword><keyword>TCF Transcription
Factors/metabolism</keyword><keyword>Wnt
Proteins/agonists/antagonists &amp;
inhibitors/*metabolism</keyword><keyword>beta
Catenin/*metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1878-1551
(Electronic)&#xD;1534-5807
(Linking)</isbn><accession-num>19619488</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/19619488</url></related-urls></urls><custom2>PMC2861485</custom2><electronic-resource-num>10.1016/j.devcel.2009.06.016</electronic-resource-num></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(MacDonald et al., 2009)<!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</span></span></p>
<strong>Empirical Evidence</strong>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">[Incidence concordance]</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Dishevelled (DVL), a positive regulator of Wnt signaling, form the complex with FZD and lead to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (Clevers & Nusse, 2012; Jiang, Charlat, Zamponi, Yang, & Cong, 2015). </span><span style="font-family:Arial,Helvetica,sans-serif">Wnt binds to FZD and activates the Wnt signaling (Clevers & Nusse, 2012; Janda, Waghray, Levin, Thomas, & Garcia, 2012; Nile, Mukund, Stanger, Wang, & Hannoush, 2017). Wnt binding towards FZD induces the formation of the protein complex with LRP5/6 and DVL, leading to the downstream signaling activation including beta-catenin (Clevers & Nusse, 2012).</span></span> </p>
<strong>Uncertainties and Inconsistencies</strong>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Some Wnt ligands bind to FZD, leading to Wnt/beta-catenin signaling inactivation. DVL, a positive regulator of Wnt signaling, has a controversial role to promote Wnt receptor degradation (Jiang et al., 2015). DVL-dependent regulation of FZD level is involved in mTORC1 signaling suppression via Wnt/beta-catenin signaling (Zeng et al., 2018)</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">GSK3beta phosphorylates LRP6 as well as remaining GSK3 beta phosphorylates beta-catenin which would be ubiquitinated and degradated (MacDonald et al., 2009).</span></span> </p>
<h4>Quantitative Understanding of the Linkage</h4>
<p style="margin-left:18.0pt"></p>
<strong>Response-response relationship</strong>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Wnt3 promotes proliferation and survival in HUVECs (Shen et al., 2018).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">GSK3beta inhibition by 1 uM of SB216763 or 5 uM of BRD3731 results in the decreased phosphorylation and stabilization of beta-catenin (Stump et al., 2019). The level of beta-catenin is increased by the inhibition of GSK3beta kinase activity (Stump et al., 2019). GSK3beta inhibition by small interference RNA (siRNA) of GSK3beta results in the decreased phosphorylation and increased expression of beta-catenin (Stump et al., 2019).</span></span></p>
<strong>Time-scale</strong>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">FZD7 enhances the activity of canonical Wnt/beta-catenin signaling with the treatment of WNT3A for 1 to 6 hrs <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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style='mso-element:field-separator'></span></span><![endif]-->(Cao et al., 2017)<!--[if gte mso 9]><xml>
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mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The treatment with SB216763 or BRD3731, GSK3beta inhibitors, decreases phosphorylated beta-catenin and increased beta-catenin expression in 48 hours <!--[if supportFields]><span
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Stump et al., 2019)<!--[if gte mso 9]><xml>
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mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The cells are treated with GSK3beta small interference RNA (siRNA) for 48 hours to silence the expression of GSK3beta, which results in the activation of beta-catenin pathway <!--[if supportFields]><span
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Stump et al., 2019)<!--[if gte mso 9]><xml>
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style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</span></span></p>
<strong>Known modulating factors</strong>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">FZD5 can activate WNT3A/beta-catenin signaling in a dose-dependent manner <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Hua et al., 2018)<!--[if gte mso 9]><xml>
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</xml><![endif]--><!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The increase in FZD5 protein enhances cell response to WNT3A. <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Hua et al., 2018)<!--[if gte mso 9]><xml>
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</xml><![endif]--><!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. LRP5 can augment WNT3A/beta-catenin signaling in a dose-dependent manner <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Hua et al., 2018)<!--[if gte mso 9]><xml>
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</xml><![endif]--><!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The binding of Wnt and FZD induce the formation of the protein complex with the Dvl, Axin, CK1 GSK3, beta-catenin and APC to induce the beta-catenin translocation into the nucleus <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
"ＭＳＰゴシック";mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:
EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Clevers</Author><Year>2012</Year><RecNum>10</RecNum><DisplayText>(Clevers
&amp; Nusse,
2012)</DisplayText><record><rec-number>10</rec-number><foreign-keys><key
app="EN" db-id="z0t2vdzwlt05d9ewr09vwwd85sdd5wtsarsd"
timestamp="1584950464">10</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Clevers,
H.</author><author>Nusse,
R.</author></authors></contributors><auth-address>Hubrecht
Institute, KNAW and University Medical Center Utrecht, The Netherlands.
h.clevers@hubrecht.eu</auth-address><titles><title>Wnt/beta-catenin
signaling and disease</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>1192-205</pages><volume>149</volume><number>6</number><edition>2012/06/12</edition><keywords><keyword>Animals</keyword><keyword>Disease/genetics</keyword><keyword>Humans</keyword><keyword>Wnt
Proteins/*metabolism</keyword><keyword>*Wnt Signaling
Pathway</keyword><keyword>beta
Catenin/*metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun
8</date></pub-dates></dates><isbn>1097-4172
(Electronic)&#xD;0092-8674
(Linking)</isbn><accession-num>22682243</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/22682243</url></related-urls></urls><electronic-resource-num>10.1016/j.cell.2012.05.012</electronic-resource-num></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(Clevers & Nusse, 2012)<!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</span></span></p>
<strong>Known Feedforward/Feedback loops influencing this KER</strong>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Beta-catenin is required and sufficient for the sequestration of GSK3 in acidic cytoplasmic endosomes <!--[if supportFields]><span lang=EN-US style='font-size:14.0pt;
font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";mso-bidi-font-family:Times;
mso-font-kerning:0pt;mso-ansi-language:EN-US;mso-fareast-language:JA;
mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Taelman</Author><Year>2010</Year><RecNum>109</RecNum><DisplayText>(Taelman
et al., 2010)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key
app="EN" db-id="z0t2vdzwlt05d9ewr09vwwd85sdd5wtsarsd"
timestamp="1584950464">109</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Taelman,
V. F.</author><author>Dobrowolski,
R.</author><author>Plouhinec, J.
L.</author><author>Fuentealba, L.
C.</author><author>Vorwald, P.
P.</author><author>Gumper, I.</author><author>Sabatini,
D. D.</author><author>De Robertis, E.
M.</author></authors></contributors><auth-address>Howard
Hughes Medical Institute and Department of Biological Chemistry, University of
California, Los Angeles, Los Angeles, CA 90095-1662,
USA.</auth-address><titles><title>Wnt signaling requires
sequestration of glycogen synthase kinase 3 inside multivesicular
endosomes</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>1136-48</pages><volume>143</volume><number>7</number><edition>2010/12/25</edition><keywords><keyword>Animals</keyword><keyword>Cell
Line</keyword><keyword>Embryo,
Nonmammalian/metabolism</keyword><keyword>Glycogen Synthase Kinase
3/*metabolism</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Multivesicular
Bodies/*metabolism/ultrastructure</keyword><keyword>Phosphorylation</keyword><keyword>Protein
Stability</keyword><keyword>*Signal Transduction</keyword><keyword>Wnt
Proteins/*metabolism</keyword><keyword>Xenopus</keyword></keywords><dates><year>2010</year><pub-dates><date>Dec
23</date></pub-dates></dates><isbn>1097-4172
(Electronic)&#xD;0092-8674
(Linking)</isbn><accession-num>21183076</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/21183076</url></related-urls></urls><custom2>PMC3022472</custom2><electronic-resource-num>10.1016/j.cell.2010.11.034</electronic-resource-num></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(Taelman et al., 2010)<!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. Beta-catenin, of which level increases in Wnt signaling, facilitates GSK3 sequestration leading to feed-forward loop formation <!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE
<EndNote><Cite><Author>Taelman</Author><Year>2010</Year><RecNum>109</RecNum><DisplayText>(Taelman
et al.,
2010)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key
app="EN" db-id="z0t2vdzwlt05d9ewr09vwwd85sdd5wtsarsd"
timestamp="1584950464">109</key></foreign-keys><ref-type
name="Journal
Article">17</ref-type><contributors><authors><author>Taelman,
V. F.</author><author>Dobrowolski, R.</author><author>Plouhinec,
J. L.</author><author>Fuentealba, L.
C.</author><author>Vorwald, P. P.</author><author>Gumper,
I.</author><author>Sabatini, D. D.</author><author>De
Robertis, E.
M.</author></authors></contributors><auth-address>Howard
Hughes Medical Institute and Department of Biological Chemistry, University of
California, Los Angeles, Los Angeles, CA 90095-1662,
USA.</auth-address><titles><title>Wnt signaling requires
sequestration of glycogen synthase kinase 3 inside multivesicular
endosomes</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>1136-48</pages><volume>143</volume><number>7</number><edition>2010/12/25</edition><keywords><keyword>Animals</keyword><keyword>Cell
Line</keyword><keyword>Embryo,
Nonmammalian/metabolism</keyword><keyword>Glycogen Synthase Kinase
3/*metabolism</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Multivesicular
Bodies/*metabolism/ultrastructure</keyword><keyword>Phosphorylation</keyword><keyword>Protein
Stability</keyword><keyword>*Signal
Transduction</keyword><keyword>Wnt Proteins/*metabolism</keyword><keyword>Xenopus</keyword></keywords><dates><year>2010</year><pub-dates><date>Dec
23</date></pub-dates></dates><isbn>1097-4172
(Electronic)&#xD;0092-8674
(Linking)</isbn><accession-num>21183076</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/21183076</url></related-urls></urls><custom2>PMC3022472</custom2><electronic-resource-num>10.1016/j.cell.2010.11.034</electronic-resource-num></record></Cite></EndNote><span
style='mso-element:field-separator'></span></span><![endif]-->(Taelman et al., 2010)<!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The Wnt ligand is antagonized with secreted Frizzled-related proteins (sFRPs) and Wnt inhibitory protein (WIF), both of which can bind Wnts and inhibit interactions between WNT and FZD <!--[if supportFields]><span lang=EN-US style='font-size:14.0pt;
font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";mso-bidi-font-family:Times;
mso-font-kerning:0pt;mso-ansi-language:EN-US;mso-fareast-language:JA;
mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Bovolenta, Esteve, Ruiz, Cisneros, & Lopez-Rios, 2008; Clevers & Nusse, 2012)<!--[if gte mso 9]><xml>
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</xml><![endif]--><!--[if supportFields]><span lang=EN-US
style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:"ＭＳＰゴシック";
mso-bidi-font-family:Times;mso-font-kerning:0pt;mso-ansi-language:EN-US;
mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The Dickkopf 1 (DKK1) can disrupts Wnt-induced FZD-LRP6 complex formation <!--[if supportFields]><span
lang=EN-US style='font-size:14.0pt;font-family:Times;mso-fareast-font-family:
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EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml>
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</xml><![endif]><span style='mso-element:field-end'></span><span
style='mso-element:field-separator'></span></span><![endif]-->(Clevers & Nusse, 2012; Ellwanger et al., 2008; Semenov, Zhang, & He, 2008)<!--[if gte mso 9]><xml>
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<h4>References</h4>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Bovolenta, P., Esteve, P., Ruiz, J. M., Cisneros, E., & Lopez-Rios, J. (2008). Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. <em>J Cell Sci, 121</em>(Pt 6), 737-746. doi:10.1242/jcs.026096</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Cao, T. T., Xiang, D., Liu, B. L., Huang, T. X., Tan, B. B., Zeng, C. M., . . . Fu, L. (2017). FZD7 is a novel prognostic marker and promotes tumor metastasis via WNT and EMT signaling pathways in esophageal squamous cell carcinoma. <em>Oncotarget, 8</em>(39), 65957-65968. doi:10.18632/oncotarget.19586</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. <em>Cell, 149</em>(6), 1192-1205. doi:10.1016/j.cell.2012.05.012</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Ellwanger, K., Saito, H., Clement-Lacroix, P., Maltry, N., Niedermeyer, J., Lee, W. K., . . . Niehrs, C. (2008). Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. <em>Mol Cell Biol, 28</em>(15), 4875-4882. doi:10.1128/MCB.00222-08</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hatsell, S., Rowlands, T., Hiremath, M., & Cowin, P. (2003). Beta-catenin and Tcfs in mammary development and cancer. <em>J Mammary Gland Biol Neoplasia, 8</em>(2), 145-158. Retrieved from <a href="https://www.ncbi.nlm.nih.gov/pubmed/14635791">https://www.ncbi.nlm.nih.gov/pubmed/14635791</a></span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Hua, Y., Yang, Y., Li, Q., He, X., Zhu, W., Wang, J., & Gan, X. (2018). Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/beta-catenin pathway. <em>J Biol Chem, 293</em>(51), 19710-19724. doi:10.1074/jbc.RA118.004434</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C., & Garcia, K. C. (2012). Structural basis of Wnt recognition by Frizzled. <em>Science, 337</em>(6090), 59-64. doi:10.1126/science.1222879</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Jiang, X., Charlat, O., Zamponi, R., Yang, Y., & Cong, F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. <em>Mol Cell, 58</em>(3), 522-533. doi:10.1016/j.molcel.2015.03.015</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. <em>Dev Cell, 17</em>(1), 9-26. doi:10.1016/j.devcel.2009.06.016</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Nile, A. H., Mukund, S., Stanger, K., Wang, W., & Hannoush, R. N. (2017). Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. <em>Proc Natl Acad Sci U S A, 114</em>(16), 4147-4152. doi:10.1073/pnas.1618293114</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, Kaplan JB, Chae YK, Giles FJ. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017 May 5;10(1):101. doi: 10.1186/s13045-017-0471-6. PMID: 28476164; PMCID: PMC5420131.</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Semenov, M. V., Zhang, X., & He, X. (2008). DKK1 antagonizes Wnt signaling without promotion of LRP6 internalization and degradation. <em>J Biol Chem, 283</em>(31), 21427-21432. doi:10.1074/jbc.M800014200</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Shen, M., Bai, D., Liu, B., Lu, X., Hou, R., Zeng, C., . . . Yin, T. (2018). Dysregulated Txnip-ROS-Wnt axis contributes to the impaired ischemic heart repair in diabetic mice. <em>Biochimica et biophysica acta. Molecular basis of disease, 1864</em>(12), 3735-3745. doi:10.1016/j.bbadis.2018.09.029</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Stump, B., Shrestha, S., Lamattina, A. M., Louis, P. H., Cho, W., Perrella, M. A., . . . El-Chemaly, S. (2019). Glycogen synthase kinase 3-beta inhibition induces lymphangiogenesis through beta-catenin-dependent and mTOR-independent pathways. PLoS One, 14(4), e0213831. doi:10.1371/journal.pone.0213831</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Taelman, V. F., Dobrowolski, R., Plouhinec, J. L., Fuentealba, L. C., Vorwald, P. P., Gumper, I., . . . De Robertis, E. M. (2010). Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. <em>Cell, 143</em>(7), 1136-1148. doi:10.1016/j.cell.2010.11.034</span></span></p>
<p style="margin-left:40px"><span style="font-size:12px"><span style="font-family:Arial,Helvetica,sans-serif">Zeng, H., Lu, B., Zamponi, R., Yang, Z., Wetzel, K., Loureiro, J., . . . Cong, F. (2018). mTORC1 signaling suppresses Wnt/beta-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level. <em>Proc Natl Acad Sci U S A, 115</em>(44), E10362-E10369. doi:10.1073/pnas.1808575115</span></span></p>
<p> </p>
</div>
<div>
<h4><a href="/relationships/3199">Relationship: 3199: beta-catenin activation leads to EMT</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/298">Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>adjacent</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<ul>
<li>The inhibition of c-MET decreases the expression of beta-catenin and Snail in human diffuse-type gastric cancer (<em>Homo sapiens</em>) (Sohn et al., 2019).</li>
<li>The treatment with garcinol decreases the expression of beta-catenin and ZEB1/ZEB2 in human breast cancer cells (<em>Homo sapiens</em>) (Ahmad et al., 2012).</li>
<li>Zeb1 activation leads to EMT via Prex1 activation in NCH421k, NCH441, and NCH644 human glioblastoma model cells (<em>Homo sapien</em>s) (Rosmaninho et al., 2018).</li>
<li>Zeb1 siRNA induced the suppression of EMT in SGC-7901 human gastric cancer cell line (<em>Homo sapiens</em>) (Xue et al., 2019). Snail induces EMT in SAS and HSC-4 human head and neck squamous cancer cells (<em>Homo sapiens</em>) (Ota et al., 2016).</li>
<li>Snail induces EMT in B16-F10 murine melanoma cells (<em>Mus musculus</em>) (Kudo-Saito, Shirako, Takeuchi, & Kawakami, 2009; Wang, Shi, Chai, Ying, & Zhou, 2013).</li>
<li>Twist1 is related to EMT in MCF-7 and MDA-MB-231 human breast cancer cell lines (<em>Homo sapiens</em>) (Menendez-Menendez et al., 2019).</li>
<li>Twist induces EMT in Huh7 human hepatocellular carcinoma cell lines (<em>Homo sapiens</em>) (Hu et al., 2019).</li>
</ul>
<h4>Key Event Relationship Description</h4>
<p>Beta-catenin activation, of which mechanism include the stabilization of the dephosphorylated beta-catenin and translocation of beta-catenin into the nucleus, induce the formation of beta-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman, Montes de Oca, Pal, & Afaq, 2017; Sohn et al., 2019; Yang et al., 2019).</p>
<p>EMT-related transcription factors including Snail, ZEB and Twist are up-regulated in cancer cells (Diaz, Vinas-Castells, & Garcia de Herreros, 2014). The transcription factors such as Snail, ZEB and Twist bind to E-cadherin (CDH1) promoter and inhibit the CDH1 transcription via the consensus E-boxes (5’-CACCTG-3’ or 5’-CAGGTG-3’), which leads to EMT (Diaz et al., 2014).</p>
<h4>Evidence Supporting this KER</h4>
<strong>Biological Plausibility</strong>
<p>The treatment of human gastric cancer cells with INC280, which inhibits c-MET overexpressed in diffuse-type gastric cancer with poor prognosis, shows downregulation in beta-catenin and Snail expression,(Sohn et al., 2019).</p>
<p>The treatment with garcinol, a polyisoprenylated benzophenone derivative that is obtained from <em>Garcinia indica</em> extract, induced ZEB1 and ZEB2 down-regulation, increase in phosphorylated beta-catenin, and decrease in nuclear beta-catenin in human breast cancer cells (Ahmad et al., 2012).</p>
<p>Sortilin, a member of the Vps10p sorting receptor family which is highly expressed in high-grade malignant glioma, positively regulates GSK-3beta/beta-catenin/Twist signaling pathway in glioblastoma (Yang et al., 2019).</p>
<p>TM4SF1 promotes EMT via Wnt/beta-catenin/SOX2 pathway in colorectal cancer (Yang et al., 2020).</p>
<p>The transcription factors such as Snail, Zeb, and Twist inhibit the CDH1 expression through their binding towards the promoter of CDH1, which leads to inhibition of cell adhesion and EMT (Diaz et al., 2014)</p>
<strong>Empirical Evidence</strong>
<p>[Dose concordance]</p>
<p>The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in a decrease in beta-catenin and Twist expression in human glioblastoma cells (Yang et al., 2019).</p>
<p>[Time concordance]</p>
<p>The complex of beta-catenin and TCF4 induces epithelial-mesenchymal transition (EMT)-activator ZEB (Sanchez-Tillo E et al., 2011).</p>
<p>[Incidence concordance]</p>
<p>The inhibition of c-MET, which is overexpressed in diffuse-type gastric cancer, induced an increase in phosphorylated beta-catenin, decrease in beta-catenin and Snail (Sohn et al., 2019).</p>
<p>The garcinol, which has an anti-cancer effect, increases phosphorylated beta-catenin, decreases beta-catenin and ZEB1/ZEB2, and inhibits EMT (Ahmad et al., 2012).</p>
<p>Histone deacetylase inhibitors affect EMT-related transcription factors including ZEB, Twist, and Snail (Wawruszak et al., 2019).</p>
<p>Snail and Zeb induces EMT and suppress E-cadherin (CDH1) (Batlle et al., 2000; Diaz et al., 2014; Peinado, Olmeda, & Cano, 2007).</p>
<strong>Uncertainties and Inconsistencies</strong>
<p>It is possible that the inhibition of ZEB1 and ZEB2 by garcinol treatment is caused by down-regulation of NFkappaB and Wnt/beta-catenin signaling (Ahmad et al., 2012).</p>
<p>The EMT is induced different transcription factors other than Zeb, Twist, and Snail, which includes E47 and KLF8 (Diaz et al., 2014).</p>
<p>Zeb, Twist, and Snail may activate or inactivate different genes or molecules to induce phenomena related to EMT and other phenomena other than EMT (Li & Balazsi, 2018).</p>
<h4>Quantitative Understanding of the Linkage</h4>
<strong>Response-response relationship</strong>
<p>The treatment with AF38469, a sortilin inhibitor, in 0, 100, 200, 400, 800, and 1600 nM concentration inhibited beta-catenin and Twist (EMT regulator) expression dose-dependently in human glioblastoma cells (Yang et al., 2019).</p>
<p></p>
<p>Snail (SNAI1, a key transcription factor of EMT induced by beta-catenin) mRNA is methylated, and <em>N<sup>6</sup></em>-methyladenosine (m<sup>6</sup>A) in its coding region (CDS) and 3’ untranslated region (3’UTR) are significantly enriched during EMT progression (Lin et al., 2019). The m<sup>6</sup>A enrichment fold of <em>SNAI1</em> mRNA in EMT cells is about 2.3-fold greater than in control cells (Lin et al., 2019).</p>
<strong>Time-scale</strong>
<p>Nuclear accumulation of beta-catenin induces endogenous ZEB1 in 15 and 30 min (Sanchez-Tillo E et al., 2011).</p>
<p>The treatment with 25 uM of garcinol for 48 hours induced an increase in phosphorylated beta-catenin and decreased nuclear beta-catenin protein and ZEB1/ZEB2 mRNA in human breast cancer cells (Ahmad et al., 2012).</p>
<p>The treatment with AF38469, a sortilin inhibitor, for 0, 2, 4, 8, 16, or 24 hours shows that the expression of beta-catenin and Twist decrease in 8 hours followed by the subsequent decrease in 16 and 24 hours in human glioblastoma cells (Yang et al., 2019).</p>
<p>Snail (SNAI1) transfection for 48 hours induces the repression of E-cadherin (CDH1) protein expression (Lin et al., 2019).</p>
<p>SNAI1 mRNA in polysome is up-regulated in EMT-undergoing HeLa cells treated with 10 ng/ml of TGF-beta for 3 days compared with control cells (Lin et al., 2019).</p>
<strong>Known modulating factors</strong>
<p>The proto-oncogene MET regulates beta-catenin and Snail expression (Sohn et al., 2019).</p>
<p>The inhibition of GSK3beta by SB216763 induced expression of beta-catenin and Twist, as well as mesenchymal markers such as N-cadherin, vimentin, and MMP9 (Yang et al., 2019).</p>
<p>The decrease in E-cadherin (CDH1), a cell adhesion molecule, is related to EMT (Diaz et al., 2014).</p>
<p>Methyltransferase-like 3 (METTL3) modulates methylation of Snail (SNAI1) mRNA and EMT (Lin et al., 2019).</p>
<p>The binding of beta-catenin to members of the TCF/LEF family transcription factors increase gene expression related to EMT such as Twist and decrease E-cadherin protein expression (Qualtrough, Rees, Speight, Williams, & Paraskeva, 2015).</p>
<p> </p>
<strong>Known Feedforward/Feedback loops influencing this KER</strong>
<p>The inhibited expression of phosphorylated GSK3beta, beta-catenin, and Twist by sortilin inhibition is reversed by GSK3beta inhibition. Furthermore, twist overexpression by lentivirus increased the inhibited expression of N-cadherin, MMP9, and vimentin and reverses the inhibitory effect of AF38469 on sortilin, which suggests that sortilin induces glioblastoma invasion mainly via GSK3beta/beta-catenin/Twist induced mesenchymal transition (Yang et al., 2019).</p>
<p>The inhibition of Hedgehog signaling pathway with cyclopamine reduces beta-catenin-TCF transcriptional activity, decreases the Twist expression, induces E-cadherin expression, and inhibits EMT (Qualtrough et al., 2015).</p>
<h4>References</h4>
<p>Ahmad, A., Sarkar, S. H., Bitar, B., Ali, S., Aboukameel, A., Sethi, S., . . . Sarkar, F. H. (2012). Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. <em>Mol Cancer Ther, 11</em>(10), 2193-2201. doi:10.1158/1535-7163.MCT-12-0232-T</p>
<p>Batlle, E., Sancho, E., Francí, C., Domínguez, D., Monfar, M., Baulida, J., & García de Herreros, A. (2000). The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. <em>Nature Cell Biology, 2</em>(2), 84-89. doi:10.1038/35000034</p>
<p>Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. <em>Cell, 149</em>(6), 1192-1205. doi:10.1016/j.cell.2012.05.012</p>
<p>Diaz, V. M., Vinas-Castells, R., & Garcia de Herreros, A. (2014). Regulation of the protein stability of EMT transcription factors. <em>Cell Adh Migr, 8</em>(4), 418-428. doi:10.4161/19336918.2014.969998</p>
<p>Hu, B., Cheng, J. W., Hu, J. W., Li, H., Ma, X. L., Tang, W. G., . . . Yang, X. R. (2019). KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition. <em>Journal of Cancer, 10</em>(17), 3914-3925. doi:10.7150/jca.31448</p>
<p>Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. <em>Cancer Cell, 15</em>(3), 195-206. doi:<a href="https://doi.org/10.1016/j.ccr.2009.01.023">10.1016/j.ccr.2009.01.023</a></p>
<p>Li, C., & Balazsi, G. (2018). A landscape view on the interplay between EMT and cancer metastasis. <em>NPJ Syst Biol Appl, 4</em>, 34. doi:10.1038/s41540-018-0068-x</p>
<p>Lin, X., Chai, G., Wu, Y., Li, J., Chen, F., Liu, J., . . . Wang, H. (2019). RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. <em>Nat Commun, 10</em>(1), 2065. doi:10.1038/s41467-019-09865-9</p>
<p>Menendez-Menendez, J., Hermida-Prado, F., Granda-Diaz, R., Gonzalez, A., Garcia-Pedrero, J. M., Del-Rio-Ibisate, N., . . . Martinez-Campa, C. (2019). Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin. <em>Cancers (Basel), 11</em>(7). doi:10.3390/cancers11071011</p>
<p>Ota, I., Masui, T., Kurihara, M., Yook, J. I., Mikami, S., Kimura, T., . . . Kitahara, T. (2016). Snail-induced EMT promotes cancer stem cell-like properties in head and neck cancer cells. <em>Oncol Rep, 35</em>(1), 261-266. doi:10.3892/or.2015.4348</p>
<p>Pearlman, R. L., Montes de Oca, M. K., Pal, H. C., & Afaq, F. (2017). Potential therapeutic targets of epithelial-mesenchymal transition in melanoma. <em>Cancer Lett, 391</em>, 125-140. doi:10.1016/j.canlet.2017.01.029</p>
<p>Peinado, H., Olmeda, D., & Cano, A. (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? <em>Nat Rev Cancer, 7</em>(6), 415-428. doi:10.1038/nrc2131</p>
<p>Qualtrough, D., Rees, P., Speight, B., Williams, A. C., & Paraskeva, C. (2015). The Hedgehog Inhibitor Cyclopamine Reduces beta-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells. <em>Cancers (Basel), 7</em>(3), 1885-1899. doi:10.3390/cancers7030867</p>
<p>Rosmaninho, P., Mükusch, S., Piscopo, V., Teixeira, V., Raposo, A. A., Warta, R., . . . Castro, D. S. (2018). Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion. <em>The EMBO Journal, 37</em>(15), e97115. doi:10.15252/embj.201797115</p>
<p>Sanchez-Tillo E, de Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A. beta-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. <em>Proc Natl Acad Sci U S A,</em> 2011;108(48):19204-9.</p>
<p>Sohn, S. H., Kim, B., Sul, H. J., Kim, Y. J., Kim, H. S., Kim, H., . . . Zang, D. Y. (2019). INC280 inhibits Wnt/beta-catenin and EMT signaling pathways and its induce apoptosis in diffuse gastric cancer positive for c-MET amplification. <em>BMC Res Notes, 12</em>(1), 125. doi:10.1186/s13104-019-4163-x</p>
<p>Tang Q, Chen J, Di Z, Yuan W, Zhou Z, Liu Z, Han S, Liu Y, Ying G, Shu X, Di M. TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer. J Exp Clin Cancer Res. 2020 Nov 5;39(1):232. doi: 10.1186/s13046-020-01690-z. PMID: 33153498; PMCID: PMC7643364.</p>
<p>Wang, Y., Shi, J., Chai, K., Ying, X., & Zhou, B. P. (2013). The Role of Snail in EMT and Tumorigenesis. <em>Current cancer drug targets, 13</em>(9), 963-972. doi: 10.2174/15680096113136660102</p>
<p>Wawruszak, A., Kalafut, J., Okon, E., Czapinski, J., Halasa, M., Przybyszewska, A., . . . Stepulak, A. (2019). Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells. <em>Cancers (Basel), 11</em>(2). doi:10.3390/cancers11020148</p>
<p>Xue, Y., Zhang, L., Zhu, Y., Ke, X., Wang, Q., & Min, H. (2019). Regulation of Proliferation and Epithelial-to-Mesenchymal Transition (EMT) of Gastric Cancer by ZEB1 via Modulating Wnt5a and Related Mechanisms. <em>Medical science monitor : international medical journal of experimental and clinical research, 25</em>, 1663-1670. doi:10.12659/MSM.912338</p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Yang, W., Wu, P. F., Ma, J. X., Liao, M. J., Wang, X. H., Xu, L. S., . . . Yi, L. (2019). Sortilin promotes glioblastoma invasion and mesenchymal transition through GSK-3beta/beta-catenin/twist pathway. <em>Cell Death Dis, 10</em>(3), 208. doi:10.1038/s41419-019-1449-9</span></span></p>
</div>
<div>
<h4><a href="/relationships/3200">Relationship: 3200: EMT leads to Resistant gastric cancer</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/298">Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td>
<td>adjacent</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
<strong>Taxonomic Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Homo sapiens</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Life Stage Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>All life stages</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<strong>Sex Applicability</strong>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<p>EMT induces cancer invasion, metastasis (<em>Homo sapiens</em>)(<a href="#_ENREF_128" title="Zhang, 2015 #64">P. Zhang et al., 2015</a>).</p>
<p>EMT is related to cancer drug resistance in MCF-7 human breast cancer cells (<em>Homo sapiens</em>)(<a href="#_ENREF_19" title="Du, 2016 #57">B. Du & Shim, 2016</a>).</p>
<h4>Key Event Relationship Description</h4>
<p>Some population of the cells exhibiting EMT demonstrates the feature of cancer stem cells (CSCs), which are related to cancer malignancy (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>; <a href="#_ENREF_92" title="Tanabe, 2015 #131">Shihori Tanabe, 2015a</a>, <a href="#_ENREF_94" title="Tanabe, 2015 #130">2015b</a>; <a href="#_ENREF_98" title="Tanabe, 2015 #132">Tanabe, Aoyagi, Yokozaki, & Sasaki, 2015</a>).</p>
<p>EMT phenomenon is related to cancer metastasis and cancer therapy resistance (<a href="#_ENREF_83" title="Smith, 2016 #69">Smith & Bhowmick, 2016</a>; <a href="#_ENREF_90" title="Tanabe, 2013 #133">Tanabe, 2013</a>). The increased expression of enzymes that degrade the extracellular matrix components and the decrease in adhesion to the basement membrane in EMT induces the cell to escape from the basement membrane and metastasis (<a href="#_ENREF_83" title="Smith, 2016 #69">Smith & Bhowmick, 2016</a>). Morphological changes observed during EMT are associated with therapy resistance (<a href="#_ENREF_83" title="Smith, 2016 #69">Smith & Bhowmick, 2016</a>).</p>
<h4>Evidence Supporting this KER</h4>
<strong>Biological Plausibility</strong>
<p>The morphological and physiological changes associated with EMT are involved in invasiveness and drug resistance (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>). The EMT-activated particular carcinoma cells in primary tumors invade the surrounding stroma (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>). The EMT –activated carcinoma cells interact with the surrounding extracellular matrix protein to induce focal adhesion kinase and extracellular signal-related kinase activation, followed by the transforming growth factor-beta (TGFbeta) and canonical and/or noncanonical Wnt pathways to induce cancer stem cell (CSC) properties which contribute to the drug resistance (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<p>EMT-associated down-regulation of multiple apoptotic signaling pathways induces drug efflux and slows cell proliferation to induce the general resistance of carcinoma cells to anti-cancer drugs (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<p>Snail, an EMT-related transcription factor, induces the expression of the AXL receptor tyrosine kinase, which enables the cancer cells to survive by the activation of AXL signaling triggered by the binding of its ligand growth arrest-specific protein 6 (GAS6)(<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<p>The EMT-activated cells evade the lethal effect of cytotoxic T cells, which include the elevated expression of programmed cell death 1 ligand (PD-L1) which binds to the programmed cell death protein 1 (PD-1) inhibitory immune-checkpoint receptor on the cell surface of cytotoxic T cells (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<strong>Empirical Evidence</strong>
<p>Incidence concordance</p>
<p>Slug/Snai2, a <em>ces</em>-1-related zinc finger transcription factor gene, confers resistance to p53-mediated apoptosis of hematopoietic progenitors by repressing <em>PUMA</em> (also known as <em>BBC3</em>, encoding Bcl-2-binding component 3) (<a href="#_ENREF_33" title="Inukai, 1999 #117">Inukai et al., 1999</a>; <a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>; <a href="#_ENREF_109" title="Wu, 2005 #116">W.-S. Wu et al., 2005</a>).</p>
<p>EMT activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in the resistance to doxorubicin (<a href="#_ENREF_77" title="Saxena, 2011 #119">Saxena, Stephens, Pathak, & Rangarajan, 2011</a>; <a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>) </p>
<p>TGFbeta-1 induced EMT results in the acquisition of cancer stem cell (CSC) like properties (<a href="#_ENREF_72" title="Pirozzi, 2011 #118">Pirozzi et al., 2011</a>; <a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<p>Snail-induced EMT induces cancer metastasis and resistance to dendritic cell-mediated immunotherapy (<a href="#_ENREF_45" title="Kudo-Saito, 2009 #120">Kudo-Saito, Shirako, Takeuchi, & Kawakami, 2009</a>).</p>
<p>Zinc finger E-box-binding homeobox (ZEB1)-induced EMT results in the relief of miR-200-mediated repression of programmed cell death 1 ligand (PD-L1) expression, a major inhibitory ligand for the programmed cell death protein (PD-1) immune-checkpoint protein on CD8+ cytotoxic T lymphocyte (CTL), subsequently the CD8<sup>+</sup> T cell immunosuppression and metastasis (<a href="#_ENREF_11" title="Chen, 2014 #121">Chen et al., 2014</a>).</p>
<strong>Uncertainties and Inconsistencies</strong>
<p>The reversing process of EMT, which names as a mesenchymal-epithelial transition (MET), maybe one of the candidates for the anti-cancer therapy, where the plasticity of the cell phenotype is of importance and under investigation (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<h4>Quantitative Understanding of the Linkage</h4>
<strong>Response-response relationship</strong>
<p>Induction of EMT by TGFbeta and Twist increases the gene expression of EMT markers such as Snail, Vimentin, N-cadherin, and ABC transporters including ABCA3, ABCC1, ABCC3, and ABCC10 (<a href="#_ENREF_77" title="Saxena, 2011 #119">Saxena et al., 2011</a>).</p>
<p>Human mammary epithelial cells (HMLE) stably expressing Twist, FOXC2 or Snail demonstrates the increased cell viability compared to control HMLE in the treatment with about 0.3, 3, 30 mM of doxorubicin, dose-dependently (<a href="#_ENREF_77" title="Saxena, 2011 #119">Saxena et al., 2011</a>).</p>
<strong>Time-scale</strong>
<p>The treatment with doxorubicin for 48 hours demonstrates the increase in the cell viability in Twist/FOXC2/Snail overexpressed HMLE compared to control HMLE (<a href="#_ENREF_77" title="Saxena, 2011 #119">Saxena et al., 2011</a>).</p>
<p>The inhibition of Twist or Zeb1 with small interference RNA (siRNA) induced the inhibition of cell viability compared to control MDAMB231 cells treated with doxorubicin for 48 hours (<a href="#_ENREF_77" title="Saxena, 2011 #119">Saxena et al., 2011</a>).</p>
<strong>Known modulating factors</strong>
<p>ABC transporters that are related to drug resistance are overexpressed in the EMT-activated cells (<a href="#_ENREF_77" title="Saxena, 2011 #119">Saxena et al., 2011</a>). The expression of PD-L1, which binds to the PD-1 on the cytotoxic T cells, is up-regulated in EMT-activated cells, which results in the inhibition of cancer immunity and the resistance to cancer therapy (<a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<strong>Known Feedforward/Feedback loops influencing this KER</strong>
<p>The investigation of EMT-CSC relations is important to understand the relationship between EMT and cancer malignancy. Non-CSCs in cancer can spontaneously undergo EMT and dedifferentiate into new CSC, subsequently induce the regeneration of tumorigenic potential (<a href="#_ENREF_60" title="Marjanovic, 2013 #122">Marjanovic, Weinberg, & Chaffer, 2013</a>; <a href="#_ENREF_81" title="Shibue, 2017 #58">Shibue & Weinberg, 2017</a>).</p>
<p>The plastic CSC theory demonstrates the bidirectional conversions between non-CSCs and CSCs, which may contribute to the acquisition of cancer malignancy in EMT-activated cells (<a href="#_ENREF_60" title="Marjanovic, 2013 #122">Marjanovic et al., 2013</a>).</p>
<h4>References</h4>
<p style="margin-left:36.0pt">Chen, L., Gibbons, D. L., Goswami, S., Cortez, M. A., Ahn, Y.-H., Byers, L. A., . . . Qin, F. X.-F. (2014). Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. <em>Nature communications, 5</em>, 5241-5241. doi:10.1038/ncomms6241</p>
<p style="margin-left:36.0pt">Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. <em>Molecules, 21</em>(7). doi:10.3390/molecules21070965</p>
<p style="margin-left:36.0pt">Inukai, T., Inoue, A., Kurosawa, H., Goi, K., Shinjyo, T., Ozawa, K., . . . Look, A. T. (1999). SLUG, a ces-1-Related Zinc Finger Transcription Factor Gene with Antiapoptotic Activity, Is a Downstream Target of the E2A-HLF Oncoprotein. <em>Molecular Cell, 4</em>(3), 343-352. doi:<a href="https://doi.org/10.1016/S1097-2765(00)80336-6">https://doi.org/10.1016/S1097-2765(00)80336-6</a></p>
<p style="margin-left:36.0pt">Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. <em>Cancer Cell, 15</em>(3), 195-206. doi:<a href="https://doi.org/10.1016/j.ccr.2009.01.023">https://doi.org/10.1016/j.ccr.2009.01.023</a></p>
<p style="margin-left:36.0pt">Marjanovic, N. D., Weinberg, R. A., & Chaffer, C. L. (2013). Cell plasticity and heterogeneity in cancer. <em>Clinical chemistry, 59</em>(1), 168-179. doi:10.1373/clinchem.2012.184655</p>
<p style="margin-left:36.0pt">Pirozzi, G., Tirino, V., Camerlingo, R., Franco, R., La Rocca, A., Liguori, E., . . . Rocco, G. (2011). Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. <em>PLoS One, 6</em>(6), e21548-e21548. doi:10.1371/journal.pone.0021548</p>
<p style="margin-left:36.0pt">Saxena, M., Stephens, M. A., Pathak, H., & Rangarajan, A. (2011). Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. <em>Cell death & disease, 2</em>(7), e179-e179. doi:10.1038/cddis.2011.61</p>
<p style="margin-left:36.0pt">Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. <em>Nat Rev Clin Oncol, 14</em>(10), 611-629. doi:10.1038/nrclinonc.2017.44</p>
<p style="margin-left:36.0pt">Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in Metastasis and Therapy Resistance. <em>J Clin Med, 5</em>(2). doi:10.3390/jcm5020017</p>
<p style="margin-left:36.0pt">Tanabe, S. (2013). Perspectives of gene combinations in phenotype presentation. <em>World journal of stem cells, 5</em>(3), 61-67. doi:10.4252/wjsc.v5.i3.61</p>
<p style="margin-left:36.0pt">Tanabe, S. (2015a). Origin of cells and network information. <em>World journal of stem cells, 7</em>(3), 535-540. doi:10.4252/wjsc.v7.i3.535</p>
<p style="margin-left:36.0pt">Tanabe, S. (2015b). Signaling involved in stem cell reprogramming and differentiation. <em>World journal of stem cells, 7</em>(7), 992-998. doi:10.4252/wjsc.v7.i7.992</p>
<p style="margin-left:36.0pt">Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2015). Regulated genes in mesenchymal stem cells and gastric cancer. <em>World journal of stem cells, 7</em>(1), 208-222. doi:10.4252/wjsc.v7.i1.208</p>
<p style="margin-left:36.0pt">Wu, W.-S., Heinrichs, S., Xu, D., Garrison, S. P., Zambetti, G. P., Adams, J. M., & Look, A. T. (2005). Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing puma. <em>Cell, 123</em>(4), 641-653. doi:<a href="https://doi.org/10.1016/j.cell.2005.09.029">https://doi.org/10.1016/j.cell.2005.09.029</a></p>
<p style="margin-left:36.0pt">Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. <em>Cell Cycle, 14</em>(4), 481-487. doi:10.1080/15384101.2015.1006048</p>
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