Research for hepatocarcinogenesis and new therapeutic targets in hepatocellular carcinoma with or without HBV/HCV suppression

• Project/Area Number: 17K15932
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KAWAI-KITAHATA Fukiko 東京医科歯科大学, 医学部附属病院, 特任助教 (00755580)
• Research Collaborator: TANAKA Shinji ; TANABE Minoru ; ASAHINA Yasuhiro ; KAKINUMA Sei ; KANEKO Shun ; KAMIYA Akihide
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肝細胞癌 / 遺伝子変異 / B型肝炎 / C型肝炎 / 肝炎ウイルス / iPS細胞

Outline of Final Research Achievements

We investigated cancer-related genes and viral integration using next generation sequencing in HCC tissues.
In HBs antigen positive HCC, HBV suppression by NUCs may reduce TERT promoter mutation, but not HBV integration. In contrast, HCV eradication has a small influence on gene mutational status in HCV-related HCC. About 10% of NBNC HCC with prior HBV infection had HBV integration and these were developed from normal liver at a younger age. These results above are important and contribute to clarify the mechanisms of the genomic features including HBV integration and the underlying pathway responsible for hepatocarcinogenesis among different etiology and status of viral suppression.

Academic Significance and Societal Importance of the Research Achievements

近年課題となっているHCV排除後やHBV制御下において肝癌を発症した症例に関して癌関連遺伝子変異やウイルスDNAのヒトゲノムへの挿入を調べた。病因やウイルス制御状態により発癌過程が異なる可能性を示しその発癌機構の一端を解明したことにより、発癌予測や治療方針など臨床的な知見となり得る。

Research Products

• [Journal Article] Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients (2019)
  • 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.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5722-5722
  • DOI: 10.1038/s41598-019-42114-z
  • Peer Reviewed / Open Access
• [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.
  • Journal Title: Journal of Heptatology Volume: 印刷中 Issue: 1 Pages: 143-152
  • DOI: 10.1016/j.jhep.2019.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2072-2072
  • DOI: 10.1038/s41598-018-37430-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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.
  • Journal Title: Digestive Diseases Volume: 37 Issue: 3 Pages: 247-254
  • DOI: 10.1159/000493580
  • Peer Reviewed
• [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.
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 5 Pages: 500-511
  • DOI: 10.1111/hepr.13307
  • Peer Reviewed / Open Access
• [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.
  • Journal Title: J Med Virol Volume: in press Issue: 7 Pages: 1241-1247
  • DOI: 10.1002/jmv.24763
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1212-1218
  • DOI: 10.1111/hepr.12867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • Journal Title: J Hepatol Volume: 67 Issue: 5 Pages: 933-939
  • DOI: 10.1016/j.jhep.2017.05.028
  • Peer Reviewed / Open Access
• [Presentation] Difference of gene mutational profile among viral- and non-viral HCC with or without prior HBV infection: Results of comprehensive deep sequencing analyses of cancer genes and HBV/AAV integration (2018)
  • Author(s): Fukiko Kawai-Kitahata, Yasuhiro Asahina, Sei Kakinuma, Miyako Murakawa, Sayuri Nitta, Hiroko Nagata, Shun Kaneko, Emi Inoue, Masato Miyoshi, Tomoyuki Tsunoda, Ayako Sato, Mina Nakagawa, Yasuhiro Itsui, Seishin Azuma, Shinji Tanaka, Minoru Tanabe, Shinya Maekawa, Nobuyuki Enomoto and Mamoru Watanabe
  • Organizer: EASL The International Liver Congress 2018
  • Int'l Joint Research
• [Presentation] 肝癌の臨床検体を用いた癌関連遺伝子プロファイルと病態の解析 (2018)
  • Author(s): 北畑富貴子、朝比奈靖浩、渡辺守
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] 癌関連遺伝子変異とウイルスのヒトゲノム挿入から検討する肝炎ウイルス制御下肝細胞癌の病態 (2018)
  • Author(s): 北畑富貴子、朝比奈靖浩、渡辺守
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] Gene mutational profile and viral integration in hepatocellular carcinoma with or without HBV/HCV suppression (2018)
  • Author(s): Yasuhiro Asahina, Fukiko Kawai-Kitahata, Sei Kakinuma, Miyako Murakawa, Sayuri Nitta, Hiroko Nagata, Shun Kaneko, Emi Inoue, Masato Miyoshi, Tomoyuki Tsunoda, Ayako Sato, Mina Nakagawa, Yasuhiro Itsui, Seishin Azuma, Shinji Tanaka, Minoru Tanabe, Shinya Maekawa, Nobuyuki Enomoto and Mamoru Watanabe
  • Organizer: The Liver Meeting 2018 AASLD
  • Int'l Joint Research
• [Presentation] Genetic differences in hepatocellular carcinoma among chronic persistent hepatitis B virus (HBV) infection with or without viral suppression and prior HBV infection. (2017)
  • 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: EASL, The International Liver Congress 2017
  • Int'l Joint Research
• [Presentation] B型肝炎ウイルス制御下における肝細胞癌遺伝子変異の検討 (2017)
  • Author(s): 北畑富貴子、朝比奈靖浩、渡辺 守
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 肝炎ウイルス制御下およびB型肝炎ウイルス制御下における肝細胞癌遺伝子変異の検討 (2017)
  • Author(s): 北畑富貴子、朝比奈靖浩、田中真二、村川美也子 、新田沙由梨 、永田紘子 、金子 俊 、浅野 侑、三好正人 、角田知之 、井上恵美 、佐藤綾子 、井津井康浩 、柿沼 晴、中川美奈 、東 正新 、田邉稔、前川伸哉、榎本信幸、渡辺 守
  • Organizer: 第53回日本肝癌研究会
• [Book] 消化器・肝臓内科 (2017)
  • Author(s): 北畑富貴子、朝比奈靖浩
  • Total Pages: 124
  • Publisher: 科学評論社