Elucidation of the mechanism involved HBV persistent infection and HBV-related HCC development
Project/Area Number |
17K09406
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Gastroenterology
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Nitta Sayuri 東京医科歯科大学, 医学部附属病院, 特任助教 (20527056)
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Co-Investigator(Kenkyū-buntansha) |
柿沼 晴 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (30372444)
朝比奈 靖浩 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692)
渡辺 守 東京医科歯科大学, 高等研究院, 特別栄誉教授 (10175127)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | B型肝炎 / 自然免疫応答 / HBV / 自然免疫 / 発癌 / 慢性肝炎 / ヒトiPS細胞 / 肝癌 / 肝疾患治療 / 臨床病態解析 |
Outline of Final Research Achievements |
HBV (hepatitis B virus) infection causes chronic hepatitis, cirrhosis, and HCC (hepatocellular carcinoma). However, the mechanism involved persistent infection and HCC development are still unclear. In this study, we indicated that innate immunity activated by HBV infection suppressed HBV replication and that the activated innate immune signaling could be partly suppressed by HBV itself, suggesting that the immune evade mechanism by HBV contribute to the persistent infection and resistance to IFN therapy. It may also be associated with the difference of clinical course among the genotypes. In the study using HCC tissue samples and paired non-HCC liver samples, STING mediated signal pathway was suggested to be associated with the HCC development. These results are important for understanding the mechanism of HBV persistent infection and HCC carcinogenesis and also provide the knowledges for developing novel therapeutic agents.
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Academic Significance and Societal Importance of the Research Achievements |
本邦におけるHBV(B型肝炎ウイルス)感染者数は未だ140万人程度と非常に多い。HBVの持続感染は慢性肝炎、肝硬変、肝癌の原因となり得るが、ウイルスの完全排除は現在においても困難であることから、これらの機序解明、治療開発が急務である。本研究では、HBVの持続感染成立機序の一端を明らかにしたことで、新たな抗ウイルス薬開発の基盤となる知見を提供でき、またgenotypeによる臨床病態の差異を規定する分子機構に関連する本研究の成果はgenotypeに応じた治療戦略を開発する上で有用と考えられ、社会的意義があると考える。また、肝発癌に新たなメカニズムの関与が示唆され、学術的にも興味深いものである。
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Report
(4 results)
Research Products
(57 results)
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[Journal Article] Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts2020
Author(s)
Sato A, Kakinuma S, Miyoshi M, Kamiya A, Tsunoda T, Kaneko S, Tsuchiya J, Shimizu T, Takeichi E, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Koshikawa N, Seiki S, Nakauchi H, Asahina Y, Watanabe M.
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Journal Title
Hepatology Communications
Volume: 4
Issue: 2
Pages: 235-254
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Comprehensive genetic analysis of cholangiolocellular carcinoma with a coexistent hepatocellular carcinoma‐like area and metachronous hepatocellular carcinoma2019
Author(s)
Kawai-Kitahata F, Asahina Y, Kaneko S, Tsuchiya J, Sato A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Tanabe M, Sugawara E, Takemoto A, Ojima H, Sakamoto M, Muraoka M, Takano S, Maekawa S, Enomoto N and Watanabe M.
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Journal Title
Hepatology Research
Volume: 49
Issue: 12
Pages: 1466-1474
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] .Association of serum IFN-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents.2019
Author(s)
Emi Inoue-Shinomiya, Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Masato Miyoshi, Sayuri Nitta, Fukiko Kawai-Kitahata, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Kazumoto Murata, Masashi Mizokami, Mamoru Watanabe.
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Journal Title
Hepatology Research
Volume: 印刷中
Issue: 5
Pages: 500-511
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients2019
Author(s)
Nitta S, Asahina Y, Kato T, Tsuchiya J, Inoue-Shinomiya E, Sato A, Tsunoda T, Miyoshi M, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Hikita H, Takehara T, Watanabe M.
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Journal Title
Scientific Reports
Volume: 9
Issue: 1
Pages: 5722-5722
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Loss of Fibrocystin Promotes Interleukin-8-Dependent Proliferation and CTGF Production of Biliary Epithelium.2019
Author(s)
Tsunoda T, Kakinuma S, Miyoshi M, Kamiya A, Kaneko S, Sato A, Tsuchiya J, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Sogo T, Komatsu H, Mukouchi R, Inui A, Fujisawa T, Nakauchi H, Asahina Y, Watanabe M.
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Journal Title
Journal of Heptatology
Volume: 印刷中
Issue: 1
Pages: 143-152
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells.2019
Author(s)
Miyoshi M, Kakinuma S, Kamiya A, Tsunoda T, Tsuchiya J, Sato A, Kaneko S, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Nakauchi H, Asahina Y, Watanabe M.
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Journal Title
Scientific Reports
Volume: 9
Issue: 1
Pages: 2072-2072
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Diabetic Retinopathy as a Risk Factor Associated with the Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.2019
Author(s)
Azuma S, Asahina Y, Kakinuma S, Azuma K, Miyoshi M, Inoue E, Tsunoda T, Sato A, Kaneko S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Tomita M, Nakagawa M, Watanabe M.
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Journal Title
Digestive Diseases
Volume: 37
Issue: 3
Pages: 247-254
DOI
Related Report
Peer Reviewed
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[Journal Article] Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.2017
Author(s)
Nagata H, Nakagawa M, Asahina Y, Sato A, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Nouchi T, Sakai H, Tomita M, Watanabe M
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Journal Title
J Hepatol
Volume: 67
Issue: 5
Pages: 933-939
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin.2017
Author(s)
Murakawa M, Asahina Y, Nagata H, Nakagawa M, Kakinuma S, Nitta S, Kawai-Kitahata F, Otani S, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Sato A, Itsui Y, Azuma S, Nouchi T, Furumoto Y, Asano T, Chuganji Y, Tohda S, Watanabe M.
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Journal Title
Hepatol Res
Volume: 印刷中
Issue: 11
Pages: 1212-1218
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Hepatic IFNL4 expression is associated with non-response to interferonbased therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients.2017
Author(s)
Murakawa M, Asahina Y, Kawai-Kitahata F, Nakagawa M, Nitta S, Otani S, Nagata H, Kaneko S, Asano Y, Tsunoda T, Miyoshi M, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Iijima S, Tsuchiya K, Izumi N, Tohda S, Watanabe M.
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Journal Title
J Med Virol
Volume: in press
Issue: 7
Pages: 1241-1247
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] The association of serum IFN-lambda 3 levels with liver fibrosis and hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents2019
Author(s)
Miyako Murakawa, Yasuhiro Asahina, Emi Inoue, Mina Nakagawa, Jun Tuchiya, Ayako Sato, Masato Miyoshi, Tomoyuki Tsunoda, Fukiko Kitahata-Kawai, Sayuri Nitta, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe
Organizer
EASL, The International Liver Congress 2019
Related Report
Int'l Joint Research
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[Presentation] Impact of HCV clearance on HCC development and patient survival: Propensity score-matched analysis of an ongoing database of 2173 CHC patients2019
Author(s)
MIna Nakagawa, Yasuhiro Asahina, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Msato Miyosh, Emi Inoue, Fukiko Kawai-Kitahata, MIyako Murakawa, Sayuri Nitta, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Makoto Tomita, Mamoru Watanabe
Organizer
EASL, The International Liver Congress 2019
Related Report
Int'l Joint Research
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[Presentation] The Characteristic and the Anti-HCV Reagents Susceptibility Analysis of NS5A Resistance-Associated Substitutions (RAS) Detected after DAA Treatment Failure Patients.2018
Author(s)
Sayuri Nitta, Takanobu Kato, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Masato Miyoshi, Emi Inoue-Shinomiya, Fukiko Kawai-Kitahata, Miyako Murakawa, Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Sei Kakinuma and Yasuhiro Asahina
Organizer
AASLD The LiverMeeting 2018
Related Report
Int'l Joint Research
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[Presentation] The in vitro analysis of NS5A resistance-associated substitutions (RAS) observed in DAA treatment failure patients.2018
Author(s)
Sayuri Nitta, Takanobu Kato, Jun Tuchiya, Emi Inoue-Shinomiya, Ayako Sato, Tomoyuki Tsunoda, Masato Miyoshi, Fukiko Kawai-Kitahata, Miyako Murakawa, Yasuhiro Istui, Seishin Azuma, Mina Nakagawa, Sei Kakinuma, Yasuhiro Asahina
Organizer
25th International Symposium on Hepatitis C Virus and Related Viruses
Related Report
Int'l Joint Research
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[Presentation] On-treatment higher levels of alpha-fetoprotein and M2BPGi are associated with development of hepatocellular carcinoma during nucleos(t)ide analog therapy in patients with HBV chronic infection2017
Author(s)
Murakawa M, Asahina Y, Nakagawa M, Nitta S, Kawai-Kitahata F, Nagata H, Kaneko S, Asano Y, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Sato A, Itsui Y, Kakinuma S, Azuma S, Watanabe M
Organizer
AASLD The Liver Meeting 2017
Related Report
Int'l Joint Research
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[Presentation] A novel culture model for coinfection of hepatitis B and hepatitis C viruses using human induced pluripotent stem cell-derived hepatic cells for analyses of changes in host-innate immune responses2017
Author(s)
Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Inoue-Shinomiya E, Nitta S, Sato A, Asano Y, Nagata H, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Watanabe M
Organizer
AASLD The Liver Meeting 2017
Related Report
Int'l Joint Research
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[Presentation] Evaluation of an early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C patients treated with All-Oral DAAs - propensity score-matched analysis of a prospective database -2017
Author(s)
Nakagawa M, Asahina Y, Nagata H, Kaneko S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Watanabe M
Organizer
AASLD The Liver Meeting 2017
Related Report
Int'l Joint Research
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[Presentation] Genetic differences in hepatocellular carcinoma among chronic persistent hepatitis B virus (HBV) infection with or without viral suppression and prior HBV infetion2017
Author(s)
Kawai-Kitahata F, Asahina Y, Kakinuma S, Murakawa M, Nitta S, Nagata H, Kaneko S, Otani S, Asano Y, Inoue E, Miyoshi M, Tsunoda T, Sato A, Nakagawa M, Itsui Y, Azuma S, Tanaka S, Tanabe M, Maekawa S, Enomoto N, Watanabe M
Organizer
EASL2017
Related Report
Int'l Joint Research