Identification of Factors Associated with Post-SVR Hepatocellular Carcinoma and Non-Improvement of Liver Fibrosis in Hepatitis C, and Therapeutic Implications
Project/Area Number |
20K17008
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 53010:Gastroenterology-related
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Research Institution | Hokkaido University |
Principal Investigator |
Kawagishi Naoki 北海道大学, 医学研究院, 客員研究員 (90849374)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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Keywords | HCV / 肝癌 / 肝線維化 / angiopoietin2 / HCC / アンギオポイエチン2 / DAA / 肝発がん |
Outline of Research at the Start |
慢性C型肝炎に対するSVR症例は多くが肝線維化の改善と肝発癌率の低下が期待されるが一部の症例においてはSVR後も肝線維化悪化・肝発癌が認めらえる。SVR後の肝線維化悪化、肝発癌を予測因子については十分に明らかとされていない。申請者はSVR後発癌と強く関連する1) SVR後肝線維化改善と関与するmiRNA 発現変化を複数同定し、同miRNAが肝星細胞の非活性化を介して抗線維化作用を有する事 2)肝線維化非改善と門脈圧亢進を介したangiopoietin2発現上昇が関連する事を同定した。申請者が独自に明らかにしたSVR後肝線維化悪化関連因子の病態進展への関与を明らかとし新規治療法開発の萌芽とする
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Outline of Final Research Achievements |
We identified multiple miRNA expression changes strongly associated with post-SVR HCC and involved in the improvement of liver fibrosis after SVR. We demonstrated that these miRNAs have anti-fibrotic effects through the deactivation of hepatic stellate cells. Furthermore, we investigated the potential of administering these miRNAs to a liver fibrosis model mouse, revealing their ability to suppress liver fibrosis. Additionally, we identified the association between non-improvement of liver fibrosis and increased expression of ANG2 mediated through portal hypertension. In a long-term observational study, we also reported the correlation between increased ANG2 expression and non-improvement of liver fibrosis. Considering the potential association between non-improvement of liver fibrosis and hepatocellular carcinoma, we examined the relationship between post-SVR hepatocellular carcinoma and increased ANG2 expression.
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Academic Significance and Societal Importance of the Research Achievements |
慢性C型肝炎に対する、Direct Acting Antiviral(DAA)の登場により治療の安全性・効果は飛躍的に上昇し非代償性肝硬変症例を含め大多数の症例においてウイルス学的著効(SVR)が得られるようになった。SVR症例は、多くが肝線維化の改善と肝発癌率の低下が期待されるが一部の症例においてはSVR後も肝線維化悪化・肝発癌が認めらえる。しかしながら、現在までにSVR後の肝線維化悪化、肝発癌を予測する因子については十分に明らかとされていない。今研究で得られた結果により、SVR後発癌予防、肝線維化改善のターゲットの同定と治療応用への萌芽的知見が得られた。
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Report
(4 results)
Research Products
(15 results)
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[Journal Article] Effects of nucleos(t)ide analogs on hepatitis B surface antigen reduction with interferon-lambda 3 induction in chronic hepatitis B patients2022
Author(s)
Umemura M, Ogawa K, Morikawa K, Kubo A, Tokuchi Y, Yamada R, Kitagataya T, Shigesawa T, Shimazaki T, Kimura M, Suzuki K, Nakamura A, Ohara M, Kawagishi N, Izumi T, Nakai M, Sho T, Suda G, Natsuizaka M, Ono K, Murata K, Sugiyama M, Mizokami M, Sakamoto N
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Journal Title
Hepatol Res
Volume: 52
Issue: 7
Pages: 586-596
DOI
Related Report
Peer Reviewed
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[Journal Article] Changes in the estimated renal function after hepatitis C virus eradication with direct-acting antiviral agents: Impact of changes in skeletal muscle mass2021
Author(s)
Tokuchi Y, Suda G, Kimura M, Maehara O, Kitagataya T, Ohara M, Yamada R, Shigesawa T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
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Journal Title
J Viral Hepat.
Volume: in press
Issue: 5
Pages: 755-763
DOI
Related Report
Peer Reviewed
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[Journal Article] Baseline serum angiopoietin-2 and VEGF levels predict the deterioration of the liver functional reserve during lenvatinib treatment for hepatocellular carcinoma2021
Author(s)
Shigesawa T, Suda G, Kimura M, Maehara O, Tokuchi Y, Kubo A, Yamada R, Furuya K, Baba M, Kitagataya T, Suzuki K, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
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Journal Title
PLoS One
Volume: 16(3)
Issue: 3
Pages: e0247728-e0247728
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection2021
Author(s)
Suzuki K, Suda G, Yamamoto Y, Furuya K, Baba M, Nakamura A, Miyoshi H, Kimura M, Maehara O, Yamada R, Kitagataya T, Yamamoto K, Shigesawa T, Nakamura A, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Ohnishi S, Sakamoto N
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Journal Title
J Gastroenterol.
Volume: 56
Issue: 2
Pages: 168-180
DOI
Related Report
Peer Reviewed
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