Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma
Identifieur interne : 000166 ( Istex/Corpus ); précédent : 000165; suivant : 000167Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma
Auteurs : Fatma E. Mohamed ; Rajai M. Al-Jehani ; Shane S. Minogue ; Fausto Andreola ; Alison Winstanley ; Steven W. M. Olde Damink ; Abeba Habtesion ; Massimo Malag ; Nathan Davies ; Tu Vinh Luong ; Amar P. Dhillon ; Rajeshwar P. Mookerjee ; Dipok K. Dhar ; Rajiv JalanSource :
- Liver International [ 1478-3223 ] ; 2015-03.
Abstract
Background & Aims: Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC). Toll‐like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC. Methods: Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and HCC were examined for expression of TLR7 and TLR9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human HCC cell lines was studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG‐ODN respectively) and inhibition with a specific antagonist (IRS‐954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (DEN)/nitrosomorpholine (NMOR)‐induced model of HCC. Results: TLR7 and TLR9 expression was up‐regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS‐954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumour growth in the mouse xenograft model. HCC development in the DEN/NMOR rat model was also significantly inhibited by chloroquine (P < 0.001). Conclusion: The data suggest that inhibiting TLR7 and TLR9 with IRS‐954 or chloroquine could potentially be used as a novel therapeutic approach for preventing HCC development and/or progression in susceptible patients.
Url:
DOI: 10.1111/liv.12626
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Mohamed</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>Pathology Department, Minia University, El‐Minia, Egypt</mods:affiliation></affiliation></author><author><name sortKey="Al Ehani, Rajai M" sort="Al Ehani, Rajai M" uniqKey="Al Ehani R" first="Rajai M." last="Al-Jehani">Rajai M. Al-Jehani</name><affiliation><mods:affiliation>Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Minogue, Shane S" sort="Minogue, Shane S" uniqKey="Minogue S" first="Shane S." last="Minogue">Shane S. Minogue</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Andreola, Fausto" sort="Andreola, Fausto" uniqKey="Andreola F" first="Fausto" last="Andreola">Fausto Andreola</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Winstanley, Alison" sort="Winstanley, Alison" uniqKey="Winstanley A" first="Alison" last="Winstanley">Alison Winstanley</name><affiliation><mods:affiliation>Department of Cellular Pathology, University College Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Olde Damink, Steven W M" sort="Olde Damink, Steven W M" uniqKey="Olde Damink S" first="Steven W. M." last="Olde Damink">Steven W. M. Olde Damink</name><affiliation><mods:affiliation>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Habtesion, Abeba" sort="Habtesion, Abeba" uniqKey="Habtesion A" first="Abeba" last="Habtesion">Abeba Habtesion</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Malag, Massimo" sort="Malag, Massimo" uniqKey="Malag M" first="Massimo" last="Malag">Massimo Malag</name><affiliation><mods:affiliation>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Davies, Nathan" sort="Davies, Nathan" uniqKey="Davies N" first="Nathan" last="Davies">Nathan Davies</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Luong, Tu Vinh" sort="Luong, Tu Vinh" uniqKey="Luong T" first="Tu Vinh" last="Luong">Tu Vinh Luong</name><affiliation><mods:affiliation>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Dhillon, Amar P" sort="Dhillon, Amar P" uniqKey="Dhillon A" first="Amar P." last="Dhillon">Amar P. Dhillon</name><affiliation><mods:affiliation>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Mookerjee, Rajeshwar P" sort="Mookerjee, Rajeshwar P" uniqKey="Mookerjee R" first="Rajeshwar P." last="Mookerjee">Rajeshwar P. Mookerjee</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Dhar, Dipok K" sort="Dhar, Dipok K" uniqKey="Dhar D" first="Dipok K." last="Dhar">Dipok K. Dhar</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Jalan, Rajiv" sort="Jalan, Rajiv" uniqKey="Jalan R" first="Rajiv" last="Jalan">Rajiv Jalan</name><affiliation><mods:affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>CorrespondenceProfessor Rajiv JalanUCL Institute for Liver and Digestive HealthLiver Failure GroupUpper Third Floor, UCL Medical SchoolRoyal Free Hospital, Rowland Hill StreetNW3 2PF, LondonTel: +44 2074332795Fax: +44 2074332871e‐mail:</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: r.jalan@ucl.ac.uk</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Liver International</title><title level="j" type="alt">LIVER INTERNATIONAL</title><idno type="ISSN">1478-3223</idno><idno type="eISSN">1478-3231</idno><imprint><biblScope unit="vol">35</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="1063">1063</biblScope><biblScope unit="page" to="1076">1076</biblScope><biblScope unit="page-count">14</biblScope><date type="published" when="2015-03">2015-03</date></imprint><idno type="ISSN">1478-3223</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1478-3223</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Background & Aims: Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC). Toll‐like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC. Methods: Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and HCC were examined for expression of TLR7 and TLR9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human HCC cell lines was studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG‐ODN respectively) and inhibition with a specific antagonist (IRS‐954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (DEN)/nitrosomorpholine (NMOR)‐induced model of HCC. Results: TLR7 and TLR9 expression was up‐regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS‐954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumour growth in the mouse xenograft model. HCC development in the DEN/NMOR rat model was also significantly inhibited by chloroquine (P < 0.001). Conclusion: The data suggest that inhibiting TLR7 and TLR9 with IRS‐954 or chloroquine could potentially be used as a novel therapeutic approach for preventing HCC development and/or progression in susceptible patients.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Fatma E. Mohamed</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string><json:string>Pathology Department, Minia University, El‐Minia, Egypt</json:string></affiliations></json:item><json:item><name>Rajai M. Al‐Jehani</name><affiliations><json:string>Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK</json:string></affiliations></json:item><json:item><name>Shane S. Minogue</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Fausto Andreola</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Alison Winstanley</name><affiliations><json:string>Department of Cellular Pathology, University College Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Steven W.M. Olde Damink</name><affiliations><json:string>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Abeba Habtesion</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Massimo Malagó</name><affiliations><json:string>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Nathan Davies</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Tu Vinh Luong</name><affiliations><json:string>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK</json:string></affiliations></json:item><json:item><name>Amar P. Dhillon</name><affiliations><json:string>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK</json:string></affiliations></json:item><json:item><name>Rajeshwar P. Mookerjee</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Dipok K. Dhar</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string></affiliations></json:item><json:item><name>Rajiv Jalan</name><affiliations><json:string>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</json:string><json:string>CorrespondenceProfessor Rajiv JalanUCL Institute for Liver and Digestive HealthLiver Failure GroupUpper Third Floor, UCL Medical SchoolRoyal Free Hospital, Rowland Hill StreetNW3 2PF, LondonTel: +44 2074332795Fax: +44 2074332871e‐mail:</json:string><json:string>E-mail: r.jalan@ucl.ac.uk</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>AKT</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>chloroquine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CpG‐ODN</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>DEN & NMOR</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>HCC</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>imiquimod</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IRS</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NF‐kB</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TLR</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>VEGF</value></json:item></subject><articleId><json:string>LIV12626</json:string></articleId><arkIstex>ark:/67375/WNG-SN8CS1SX-J</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Background & Aims: Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC). Toll‐like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC. Methods: Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and HCC were examined for expression of TLR7 and TLR9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human HCC cell lines was studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG‐ODN respectively) and inhibition with a specific antagonist (IRS‐954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (DEN)/nitrosomorpholine (NMOR)‐induced model of HCC. Results: TLR7 and TLR9 expression was up‐regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS‐954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumour growth in the mouse xenograft model. HCC development in the DEN/NMOR rat model was also significantly inhibited by chloroquine (P > 0.001). Conclusion: The data suggest that inhibiting TLR7 and TLR9 with IRS‐954 or chloroquine could potentially be used as a novel therapeutic approach for preventing HCC development and/or progression in susceptible patients.</abstract><qualityIndicators><score>9.88</score><pdfWordCount>6084</pdfWordCount><pdfCharCount>38207</pdfCharCount><pdfVersion>1.6</pdfVersion><pdfPageCount>14</pdfPageCount><pdfPageSize>595.276 x 782.362 pts</pdfPageSize><pdfWordsPerPage>435</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>240</abstractWordCount><abstractCharCount>1674</abstractCharCount><keywordCount>10</keywordCount></qualityIndicators><title>Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma</title><genre><json:string>article</json:string></genre><host><title>Liver International</title><language><json:string>unknown</json:string></language><doi><json:string>10.1111/(ISSN)1478-3231</json:string></doi><issn><json:string>1478-3223</json:string></issn><eissn><json:string>1478-3231</json:string></eissn><publisherId><json:string>LIV</json:string></publisherId><volume>35</volume><issue>3</issue><pages><first>1063</first><last>1076</last><total>14</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Liver Cancer</value></json:item><json:item><value>Liver Cancer</value></json:item></subject></host><ark><json:string>ark:/67375/WNG-SN8CS1SX-J</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - gastroenterology & hepatology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - clinical medicine</json:string><json:string>3 - gastroenterology & hepatology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Hepatology</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>2015</publicationDate><copyrightDate>2015</copyrightDate><doi><json:string>10.1111/liv.12626</json:string></doi><id>75F3624B5B8F5A042287B7E4169308D4B979881A</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-SN8CS1SX-J/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-SN8CS1SX-J/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/WNG-SN8CS1SX-J/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher ref="https://scientific-publisher.data.istex.fr/ark:/67375/H02-QW5Q88H5-V">Wiley Publishing Ltd</publisher><availability><licence>© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</licence></availability><date type="published" when="2015-03"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma</title><author xml:id="author-0000"><persName><forename type="first">Fatma E.</forename><surname>Mohamed</surname></persName><affiliation><orgName type="division">UCL Institute for Liver and Digestive Health</orgName>
<orgName type="institution">Royal Free Hospital</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation><affiliation><orgName type="division">Pathology Department</orgName>
<orgName type="institution">Minia University</orgName>
<address><settlement>El‐Minia</settlement>
<country key="EG" xml:lang="en">EGYPT</country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Rajai M.</forename><surname>Al‐Jehani</surname></persName><affiliation><orgName type="division">Institute for Liver and Digestive Health</orgName>
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<orgName type="institution">Royal Free Hospital</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation></author><author xml:id="author-0008"><persName><forename type="first">Nathan</forename><surname>Davies</surname></persName><affiliation><orgName type="division">UCL Institute for Liver and Digestive Health</orgName>
<orgName type="institution">Royal Free Hospital</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation></author><author xml:id="author-0009"><persName><forename type="first">Tu Vinh</forename><surname>Luong</surname></persName><affiliation><orgName type="division">Department of Cellular Pathology</orgName>
<orgName type="institution">Royal Free London NHS Foundation Trust</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation></author><author xml:id="author-0010"><persName><forename type="first">Amar P.</forename><surname>Dhillon</surname></persName><affiliation><orgName type="division">Department of Cellular Pathology</orgName>
<orgName type="institution">Royal Free London NHS Foundation Trust</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation></author><author xml:id="author-0011"><persName><forename type="first">Rajeshwar P.</forename><surname>Mookerjee</surname></persName><affiliation><orgName type="division">UCL Institute for Liver and Digestive Health</orgName>
<orgName type="institution">Royal Free Hospital</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation></author><author xml:id="author-0012"><persName><forename type="first">Dipok K.</forename><surname>Dhar</surname></persName><affiliation><orgName type="division">UCL Institute for Liver and Digestive Health</orgName>
<orgName type="institution">Royal Free Hospital</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation></author><author xml:id="author-0013" role="corresp"><persName><forename type="first">Rajiv</forename><surname>Jalan</surname></persName><affiliation><orgName type="division">UCL Institute for Liver and Digestive Health</orgName>
<orgName type="institution">Royal Free Hospital</orgName>
<address><settlement>London</settlement>
<country key="GB" xml:lang="en">UNITED KINGDOM</country></address></affiliation></author><idno type="istex">75F3624B5B8F5A042287B7E4169308D4B979881A</idno><idno type="ark">ark:/67375/WNG-SN8CS1SX-J</idno><idno type="DOI">10.1111/liv.12626</idno><idno type="unit">LIV12626</idno><idno type="toTypesetVersion">file:LIV.LIV12626.pdf</idno></analytic><monogr><title level="j" type="main">Liver International</title><title level="j" type="alt">LIVER INTERNATIONAL</title><idno type="pISSN">1478-3223</idno><idno type="eISSN">1478-3231</idno><idno type="book-DOI">10.1111/(ISSN)1478-3231</idno><idno type="book-part-DOI">10.1111/liv.2015.35.issue-3</idno><idno type="product">LIV</idno><imprint><biblScope unit="vol">35</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="1063">1063</biblScope><biblScope unit="page" to="1076">1076</biblScope><biblScope unit="page-count">14</biblScope><date type="published" when="2015-03"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.10" when="2019-12-20"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract style="main" xml:id="liv12626-abs-0001"><head>Abstract</head><head>Background & Aims</head><p>Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (<hi rend="fc">HCC</hi>). Toll‐like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether <hi rend="fc">TLR</hi>7 and <hi rend="fc">TLR</hi>9 are potential targets for prevention and progression of <hi rend="fc">HCC</hi>.</p><head>Methods</head><p>Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and <hi rend="fc">HCC</hi> were examined for expression of <hi rend="fc">TLR</hi>7 and <hi rend="fc">TLR</hi>9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human <hi rend="fc">HCC</hi> cell lines was studied following stimulation of <hi rend="fc">TLR</hi>7 and <hi rend="fc">TLR</hi>9 using agonists (imiquimod and CpG‐<hi rend="fc">ODN</hi> respectively) and inhibition with a specific antagonist (<hi rend="fc">IRS</hi>‐954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (<hi rend="fc">DEN</hi>)/nitrosomorpholine (<hi rend="fc">NMOR</hi>)‐induced model of <hi rend="fc">HCC</hi>.</p><head>Results</head><p><hi rend="fc">TLR</hi>7 and <hi rend="fc">TLR</hi>9 expression was up‐regulated in human <hi rend="fc">HCC</hi> tissue. Proliferation of HuH7 cells <hi rend="italic">in vitro</hi> increased significantly in response to stimulation of <hi rend="fc">TLR</hi>7. <hi rend="fc">TLR</hi>7 and <hi rend="fc">TLR</hi>9 inhibition using <hi rend="fc">IRS</hi>‐954 or chloroquine significantly reduced HuH7 cell proliferation <hi rend="italic">in vitro</hi> and inhibited tumour growth in the mouse xenograft model. <hi rend="fc">HCC</hi> development in the <hi rend="fc">DEN</hi>/<hi rend="fc">NMOR</hi> rat model was also significantly inhibited by chloroquine (<hi rend="italic">P</hi> < 0.001).</p><head>Conclusion</head><p>The data suggest that inhibiting <hi rend="fc">TLR</hi>7 and <hi rend="fc">TLR</hi>9 with <hi rend="fc">IRS</hi>‐954 or chloroquine could potentially be used as a novel therapeutic approach for preventing <hi rend="fc">HCC</hi> development and/or progression in susceptible patients.</p></abstract><textClass><keywords><term xml:id="liv12626-kwd-0001">AKT</term><term xml:id="liv12626-kwd-0002">chloroquine</term><term xml:id="liv12626-kwd-0003">CpG‐ODN</term><term xml:id="liv12626-kwd-0004">DEN & NMOR</term><term xml:id="liv12626-kwd-0005">HCC</term><term xml:id="liv12626-kwd-0006">imiquimod</term><term xml:id="liv12626-kwd-0007">IRS</term><term xml:id="liv12626-kwd-0008">NF‐<hi rend="fc">kB</hi></term><term xml:id="liv12626-kwd-0009">TLR</term><term xml:id="liv12626-kwd-0010">VEGF</term></keywords><keywords rend="articleCategory"><term>Liver Cancer</term></keywords><keywords rend="tocHeading1"><term>Liver Cancer</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-20" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-SN8CS1SX-J/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component type="serialArticle" version="2.0" xml:id="liv12626" xml:lang="en"><header><publicationMeta level="product"><doi origin="wiley" registered="yes">10.1111/(ISSN)1478-3231</doi><issn type="print">1478-3223</issn><issn type="electronic">1478-3231</issn><idGroup><id type="product" value="LIV"></id></idGroup><titleGroup><title sort="LIVER INTERNATIONAL" type="main">Liver International</title><title type="short">Liver Int</title></titleGroup></publicationMeta><publicationMeta level="part" position="30"><doi origin="wiley">10.1111/liv.2015.35.issue-3</doi><copyright ownership="publisher">© 2015 John Wiley & Sons A/S</copyright><numberingGroup><numbering type="journalVolume" number="35">35</numbering><numbering type="journalIssue">3</numbering></numberingGroup><coverDate startDate="2015-03">March 2015</coverDate></publicationMeta><publicationMeta level="unit" position="400" status="forIssue" type="article"><doi>10.1111/liv.12626</doi><idGroup><id type="unit" value="LIV12626"></id></idGroup><countGroup><count number="14" type="pageTotal"></count></countGroup><titleGroup><title type="articleCategory">Liver Cancer</title><title type="tocHeading1">Liver Cancer</title></titleGroup><copyright ownership="publisher">© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</copyright><eventGroup><event date="2014-03-18" type="manuscriptReceived"></event><event date="2014-06-18" type="manuscriptAccepted"></event><event agent="SPS" date="2014-07-01" type="xmlCreated"></event><event type="publishedOnlineAccepted" date="2014-07-02"></event><event type="publishedOnlineEarlyUnpaginated" date="2014-07-30"></event><event type="firstOnline" date="2014-07-30"></event><event type="publishedOnlineFinalForm" date="2015-02-11"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.7.2 mode:FullText" date="2016-01-04"></event></eventGroup><numberingGroup><numbering type="pageFirst">1063</numbering><numbering type="pageLast">1076</numbering></numberingGroup><correspondenceTo><lineatedText><line>Correspondence</line><line>Professor Rajiv Jalan</line><line>UCL Institute for Liver and Digestive Health</line><line>Liver Failure Group</line><line>Upper Third Floor, UCL Medical School</line><line>Royal Free Hospital, Rowland Hill Street</line><line>NW3 2PF, London</line><line>Tel: +44 2074332795</line><line>Fax: +44 2074332871</line><line>e‐mail: <email>r.jalan@ucl.ac.uk</email></line></lineatedText></correspondenceTo><selfCitationGroup><citation type="self" xml:id="liv12626-cit-1001"><journalTitle>Liver Int.</journalTitle> <pubYear year="2015">2015</pubYear>; <vol>35</vol>: <pageFirst>1063</pageFirst>–<pageLast>1076</pageLast></citation></selfCitationGroup><attributeValueGroup><attributeValue attribute="type" element="note" value="equal"></attributeValue></attributeValueGroup><linkGroup><link type="toTypesetVersion" href="file:LIV.LIV12626.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma</title><title type="shortAuthors">Mohamed <i>et al</i>.</title></titleGroup><creators><creator affiliationRef="#liv12626-aff-0001 #liv12626-aff-0002" creatorRole="author" xml:id="liv12626-cr-0001"><personName><givenNames>Fatma E.</givenNames> <familyName>Mohamed</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0003" creatorRole="author" xml:id="liv12626-cr-0002"><personName><givenNames>Rajai M.</givenNames> <familyName>Al‐Jehani</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0001" creatorRole="author" xml:id="liv12626-cr-0003"><personName><givenNames>Shane S.</givenNames> <familyName>Minogue</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0001" creatorRole="author" xml:id="liv12626-cr-0004"><personName><givenNames>Fausto</givenNames> <familyName>Andreola</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0004" creatorRole="author" xml:id="liv12626-cr-0005"><personName><givenNames>Alison</givenNames> <familyName>Winstanley</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0005" creatorRole="author" xml:id="liv12626-cr-0006"><personName><givenNames>Steven W.M.</givenNames> <familyName>Olde Damink</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0001" creatorRole="author" xml:id="liv12626-cr-0014"><personName><givenNames>Abeba</givenNames> <familyName>Habtesion</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0005" creatorRole="author" xml:id="liv12626-cr-0007"><personName><givenNames>Massimo</givenNames> <familyName>Malagó</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0001" creatorRole="author" xml:id="liv12626-cr-0008"><personName><givenNames>Nathan</givenNames> <familyName>Davies</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0006" creatorRole="author" xml:id="liv12626-cr-0009"><personName><givenNames>Tu Vinh</givenNames> <familyName>Luong</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0006" creatorRole="author" xml:id="liv12626-cr-0010"><personName><givenNames>Amar P.</givenNames> <familyName>Dhillon</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0001" creatorRole="author" xml:id="liv12626-cr-0011"><personName><givenNames>Rajeshwar P.</givenNames> <familyName>Mookerjee</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0001" creatorRole="author" noteRef="#liv12626-note-0001" xml:id="liv12626-cr-0012"><personName><givenNames>Dipok K.</givenNames> <familyName>Dhar</familyName></personName></creator><creator affiliationRef="#liv12626-aff-0001" corresponding="yes" creatorRole="author" noteRef="#liv12626-note-0001" xml:id="liv12626-cr-0013"><personName><givenNames>Rajiv</givenNames> <familyName>Jalan</familyName></personName></creator></creators><affiliationGroup><affiliation countryCode="GB" type="organization" xml:id="liv12626-aff-0001"><orgDiv>UCL Institute for Liver and Digestive Health</orgDiv> <orgName>Royal Free Hospital</orgName> <address><city>London</city> <country>UK</country></address></affiliation><affiliation countryCode="EG" type="organization" xml:id="liv12626-aff-0002"><orgDiv>Pathology Department</orgDiv> <orgName>Minia University</orgName> <address><city>El‐Minia</city> <country>Egypt</country></address></affiliation><affiliation countryCode="GB" type="organization" xml:id="liv12626-aff-0003"><orgDiv>Institute for Liver and Digestive Health</orgDiv> <orgName>Royal Free London NHS Foundation Trust</orgName> <address><city>London</city> <country>UK</country></address></affiliation><affiliation countryCode="GB" type="organization" xml:id="liv12626-aff-0004"><orgDiv>Department of Cellular Pathology</orgDiv> <orgName>University College Hospital</orgName> <address><city>London</city> <country>UK</country></address></affiliation><affiliation countryCode="GB" type="organization" xml:id="liv12626-aff-0005"><orgDiv>Academic Department of Surgery and Interventional Sciences</orgDiv> <orgName>Royal Free Hospital</orgName> <address><city>London</city> <country>UK</country></address></affiliation><affiliation countryCode="GB" type="organization" xml:id="liv12626-aff-0006"><orgDiv>Department of Cellular Pathology</orgDiv> <orgName>Royal Free London NHS Foundation Trust</orgName> <address><city>London</city> <country>UK</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="liv12626-kwd-0001">AKT</keyword><keyword xml:id="liv12626-kwd-0002">chloroquine</keyword><keyword xml:id="liv12626-kwd-0003">CpG‐ODN</keyword><keyword xml:id="liv12626-kwd-0004">DEN & NMOR</keyword><keyword xml:id="liv12626-kwd-0005">HCC</keyword><keyword xml:id="liv12626-kwd-0006">imiquimod</keyword><keyword xml:id="liv12626-kwd-0007">IRS</keyword><keyword xml:id="liv12626-kwd-0008">NF‐<fc>kB</fc></keyword><keyword xml:id="liv12626-kwd-0009">TLR</keyword><keyword xml:id="liv12626-kwd-0010">VEGF</keyword></keywordGroup><fundingInfo><fundingAgency>Egyptian government</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Liver Failure Group</fundingAgency></fundingInfo><fundingInfo><fundingAgency>UCL Institute for Liver and Digestive Health</fundingAgency></fundingInfo><supportingInformation><supportingInfoItem><mediaResource alt="supporting" mimeType="application/msword" href="urn-x:wiley:14783223:media:liv12626:liv12626-sup-0004-dataS1"></mediaResource><caption><b>Data S1</b>. Materials and methods.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting" mimeType="application/mspowerpoint" href="urn-x:wiley:14783223:media:liv12626:liv12626-sup-0001-FigS1"></mediaResource><caption><b>Fig. S1.</b> TLR7, TLR9 and Ki‐67 staining in liver tissue microarrays and validation set.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting" mimeType="application/mspowerpoint" href="urn-x:wiley:14783223:media:liv12626:liv12626-sup-0002-FigS2"></mediaResource><caption><b>Fig. S2.</b> Effect of different treatments on proliferation of HepG2 cells and expression of LC3B protein in HuH7 cells.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting" mimeType="application/mspowerpoint" href="urn-x:wiley:14783223:media:liv12626:liv12626-sup-0003-FigS3"></mediaResource><caption><b>Fig. S3.</b> Absence of Glypican 3 and reduced VEGF protein expression in livers of rats treated with chloroquine and absence of TLR7 and TLR9 expression in normal rat liver.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting" mimeType="application/msword" href="urn-x:wiley:14783223:media:liv12626:liv12626-sup-0005-figurelegend"></mediaResource><caption> </caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:id="liv12626-abs-0001"><title type="main">Abstract</title><section xml:id="liv12626-sec-0001"><title type="main">Background & Aims</title><p>Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (<fc>HCC</fc>). Toll‐like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether <fc>TLR</fc>7 and <fc>TLR</fc>9 are potential targets for prevention and progression of <fc>HCC</fc>.</p></section><section xml:id="liv12626-sec-0002"><title type="main">Methods</title><p>Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and <fc>HCC</fc> were examined for expression of <fc>TLR</fc>7 and <fc>TLR</fc>9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human <fc>HCC</fc> cell lines was studied following stimulation of <fc>TLR</fc>7 and <fc>TLR</fc>9 using agonists (imiquimod and CpG‐<fc>ODN</fc> respectively) and inhibition with a specific antagonist (<fc>IRS</fc>‐954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (<fc>DEN</fc>)/nitrosomorpholine (<fc>NMOR</fc>)‐induced model of <fc>HCC</fc>.</p></section><section xml:id="liv12626-sec-0003"><title type="main">Results</title><p><fc>TLR</fc>7 and <fc>TLR</fc>9 expression was up‐regulated in human <fc>HCC</fc> tissue. Proliferation of HuH7 cells <i>in vitro</i> increased significantly in response to stimulation of <fc>TLR</fc>7. <fc>TLR</fc>7 and <fc>TLR</fc>9 inhibition using <fc>IRS</fc>‐954 or chloroquine significantly reduced HuH7 cell proliferation <i>in vitro</i> and inhibited tumour growth in the mouse xenograft model. <fc>HCC</fc> development in the <fc>DEN</fc>/<fc>NMOR</fc> rat model was also significantly inhibited by chloroquine (<i>P</i> < 0.001).</p></section><section xml:id="liv12626-sec-0004"><title type="main">Conclusion</title><p>The data suggest that inhibiting <fc>TLR</fc>7 and <fc>TLR</fc>9 with <fc>IRS</fc>‐954 or chloroquine could potentially be used as a novel therapeutic approach for preventing <fc>HCC</fc> development and/or progression in susceptible patients.</p></section></abstract></abstractGroup></contentMeta><noteGroup xml:id="liv12626-ntgp-0001"><note type="equal" xml:id="liv12626-note-0001">Both authors contributed as senior author.</note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma</title></titleInfo><name type="personal"><namePart type="given">Fatma E.</namePart><namePart type="family">Mohamed</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><affiliation>Pathology Department, Minia University, El‐Minia, Egypt</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rajai M.</namePart><namePart type="family">Al‐Jehani</namePart><affiliation>Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shane S.</namePart><namePart type="family">Minogue</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fausto</namePart><namePart type="family">Andreola</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alison</namePart><namePart type="family">Winstanley</namePart><affiliation>Department of Cellular Pathology, University College Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steven W.M.</namePart><namePart type="family">Olde Damink</namePart><affiliation>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Abeba</namePart><namePart type="family">Habtesion</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Massimo</namePart><namePart type="family">Malagó</namePart><affiliation>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nathan</namePart><namePart type="family">Davies</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tu Vinh</namePart><namePart type="family">Luong</namePart><affiliation>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Amar P.</namePart><namePart type="family">Dhillon</namePart><affiliation>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rajeshwar P.</namePart><namePart type="family">Mookerjee</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dipok K.</namePart><namePart type="family">Dhar</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><description>Both authors contributed as senior author.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rajiv</namePart><namePart type="family">Jalan</namePart><affiliation>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK</affiliation><description>Both authors contributed as senior author.</description><affiliation>CorrespondenceProfessor Rajiv JalanUCL Institute for Liver and Digestive HealthLiver Failure GroupUpper Third Floor, UCL Medical SchoolRoyal Free Hospital, Rowland Hill StreetNW3 2PF, LondonTel: +44 2074332795Fax: +44 2074332871e‐mail:</affiliation><affiliation>E-mail: r.jalan@ucl.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2015-03</dateIssued><dateCreated encoding="w3cdtf">2014-07-01</dateCreated><dateCaptured encoding="w3cdtf">2014-03-18</dateCaptured><dateValid encoding="w3cdtf">2014-06-18</dateValid><edition>Liver Int. 2015; 35: 1063–1076</edition><copyrightDate encoding="w3cdtf">2015</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract>Background & Aims: Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC). Toll‐like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC. Methods: Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and HCC were examined for expression of TLR7 and TLR9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human HCC cell lines was studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG‐ODN respectively) and inhibition with a specific antagonist (IRS‐954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (DEN)/nitrosomorpholine (NMOR)‐induced model of HCC. Results: TLR7 and TLR9 expression was up‐regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS‐954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumour growth in the mouse xenograft model. HCC development in the DEN/NMOR rat model was also significantly inhibited by chloroquine (P < 0.001). Conclusion: The data suggest that inhibiting TLR7 and TLR9 with IRS‐954 or chloroquine could potentially be used as a novel therapeutic approach for preventing HCC development and/or progression in susceptible patients.</abstract><note type="additional physical form">Data S1. Materials and methods.Fig. S1. TLR7, TLR9 and Ki‐67 staining in liver tissue microarrays and validation set.Fig. S2. Effect of different treatments on proliferation of HepG2 cells and expression of LC3B protein in HuH7 cells.Fig. S3. 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