Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma
Identifieur interne : 000F59 ( Main/Exploration ); précédent : 000F58; suivant : 000F60Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma
Auteurs : Fatma E. Mohamed [Royaume-Uni, Égypte] ; Rajai M. Al-Jehani [Royaume-Uni] ; Shane S. Minogue [Royaume-Uni] ; Fausto Andreola [Royaume-Uni] ; Alison Winstanley [Royaume-Uni] ; Steven W. M. Olde Damink [Royaume-Uni] ; Abeba Habtesion [Royaume-Uni] ; Massimo Malag [Royaume-Uni] ; Nathan Davies [Royaume-Uni] ; Tu Vinh Luong [Royaume-Uni] ; Amar P. Dhillon [Royaume-Uni] ; Rajeshwar P. Mookerjee [Royaume-Uni] ; Dipok K. Dhar [Royaume-Uni] ; Rajiv Jalan [Royaume-Uni]Source :
- 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
Affiliations:
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Mohamed</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Égypte</country><wicri:regionArea>Pathology Department, Minia University, El‐Minia</wicri:regionArea><wicri:noRegion>El‐Minia</wicri:noRegion></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 wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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 wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Andreola, Fausto" sort="Andreola, Fausto" uniqKey="Andreola F" first="Fausto" last="Andreola">Fausto Andreola</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Winstanley, Alison" sort="Winstanley, Alison" uniqKey="Winstanley A" first="Alison" last="Winstanley">Alison Winstanley</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cellular Pathology, University College Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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 wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Habtesion, Abeba" sort="Habtesion, Abeba" uniqKey="Habtesion A" first="Abeba" last="Habtesion">Abeba Habtesion</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Malag, Massimo" sort="Malag, Massimo" uniqKey="Malag M" first="Massimo" last="Malag">Massimo Malag</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Academic Department of Surgery and Interventional Sciences, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Davies, Nathan" sort="Davies, Nathan" uniqKey="Davies N" first="Nathan" last="Davies">Nathan Davies</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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 wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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 wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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 wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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 wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Jalan, Rajiv" sort="Jalan, Rajiv" uniqKey="Jalan R" first="Rajiv" last="Jalan">Rajiv Jalan</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>UCL Institute for Liver and Digestive Health, Royal Free Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></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><affiliations><list><country><li>Royaume-Uni</li><li>Égypte</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Mohamed, Fatma E" sort="Mohamed, Fatma E" uniqKey="Mohamed F" first="Fatma E." last="Mohamed">Fatma E. Mohamed</name></region><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><name sortKey="Andreola, Fausto" sort="Andreola, Fausto" uniqKey="Andreola F" first="Fausto" last="Andreola">Fausto Andreola</name><name sortKey="Davies, Nathan" sort="Davies, Nathan" uniqKey="Davies N" first="Nathan" last="Davies">Nathan Davies</name><name sortKey="Dhar, Dipok K" sort="Dhar, Dipok K" uniqKey="Dhar D" first="Dipok K." last="Dhar">Dipok K. Dhar</name><name sortKey="Dhillon, Amar P" sort="Dhillon, Amar P" uniqKey="Dhillon A" first="Amar P." last="Dhillon">Amar P. Dhillon</name><name sortKey="Habtesion, Abeba" sort="Habtesion, Abeba" uniqKey="Habtesion A" first="Abeba" last="Habtesion">Abeba Habtesion</name><name sortKey="Jalan, Rajiv" sort="Jalan, Rajiv" uniqKey="Jalan R" first="Rajiv" last="Jalan">Rajiv Jalan</name><name sortKey="Jalan, Rajiv" sort="Jalan, Rajiv" uniqKey="Jalan R" first="Rajiv" last="Jalan">Rajiv Jalan</name><name sortKey="Luong, Tu Vinh" sort="Luong, Tu Vinh" uniqKey="Luong T" first="Tu Vinh" last="Luong">Tu Vinh Luong</name><name sortKey="Malag, Massimo" sort="Malag, Massimo" uniqKey="Malag M" first="Massimo" last="Malag">Massimo Malag</name><name sortKey="Minogue, Shane S" sort="Minogue, Shane S" uniqKey="Minogue S" first="Shane S." last="Minogue">Shane S. Minogue</name><name sortKey="Mookerjee, Rajeshwar P" sort="Mookerjee, Rajeshwar P" uniqKey="Mookerjee R" first="Rajeshwar P." last="Mookerjee">Rajeshwar P. Mookerjee</name><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><name sortKey="Winstanley, Alison" sort="Winstanley, Alison" uniqKey="Winstanley A" first="Alison" last="Winstanley">Alison Winstanley</name></country><country name="Égypte"><noRegion><name sortKey="Mohamed, Fatma E" sort="Mohamed, Fatma E" uniqKey="Mohamed F" first="Fatma E." last="Mohamed">Fatma E. Mohamed</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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