Research on the mechanism of hepatocarcinogenesis by long-term replication of hepatitis virus

• Project/Area Number: 16H05196
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Okayama University
• Principal Investigator: Kato Nobuyuki 岡山大学, 医歯薬学総合研究科, 教授 (40150883)
• Co-Investigator(Kenkyū-buntansha): 金 惠淑 岡山大学, 医歯薬学総合研究科, 准教授 (70314664) ; 佐藤 伸哉 岡山大学, 医歯薬学総合研究科, 助教 (80333558) ; 團迫 浩方 岡山大学, 医歯薬学総合研究科, 准教授 (80379841) ; 上田 優輝 岡山大学, 医歯薬学総合研究科, 助教 (90756074)
• Research Collaborator: SEJIMA Hiroe ; KOKU Irin ; ONOMURA Daichi ; HIRAMOTO Hiroki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: C 型肝炎ウイルス / B型肝炎ウイルス / 長期HCV複製細胞 / 遺伝子発現変動 / HBV感受性 / Exosome / C型肝炎ウイルス(HCV) / B型肝炎ウイルス(HBV) / HCV長期複製細胞 / HBV長期複製細胞 / ウイルス / 遺伝子 / 発現制御 / 感染症 / 癌 / C型肝炎ウイルス / 長期HBV複製細胞

Outline of Final Research Achievements

We studied to clarify the relation of long-term replication of HBV or HCV and hepatocarcinogenesis, and then obtained the following results. (1) We clarified that VCX2 and AGR2 contributed to the expression control of the CPB2 gene whose expression level was remarkably decreased by the long-term HCV replication. (2) We successfully established two cloned cell lines exhibiting high HBV susceptibility by the subcloning of human immortalized hepatocyte NKNT-3 cells and human hepatoma Li23 cells. (3) We identified several genes whose expression levels significantly changed before and after HBV infection. (4) We developed the purification and quantitative methods for exosome produced from cultured cells. We demonstrated that the amount of exosome produced from HBV insusceptible cells was significantly higher than that of HBV susceptible cells.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、HCVやHBV感染により高頻度に生じる肝癌の発症を未然に防ぐ方法の開発に資する知見となるので、学術的意義があるばかりでなく、難治癌の１つで我が国に多い肝癌肝癌患者に対する社会的意義も大きい。今後も継続してこの関連の研究を展開していく必要性を示す研究成果になったことは、この研究課題の大きさを物語っていると言える。

Research Products

• [Journal Article] High‐level expression of STING restricts susceptibility to HBV by mediating type III IFN induction. (2019)
  • Author(s): Dansako H, Imai H, Ueda Y, Satoh S, Shimotohno K, Kato N.
  • Journal Title: FASEB BioAdvances Volume: 1 Pages: 67-80
  • Peer Reviewed / Open Access
• [Journal Article] Acidic polysaccharides isolated from marine algae inhibit the early step of viral infection. (2019)
  • Author(s): Ueno M, Nogawa M, Siddiqui R, Watashi K, Wakita T, Kato N, Ikeda M, Okimura T, Isaka S, Oda T, Ariumi Y.
  • Journal Title: Int J Biol Macromol Volume: 124 Pages: 282-290
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Multiple antiviral activities of the antimalarial and anti-hepatitis C drug candidates N-89 and N-251 (2018)
  • Author(s): Ueda Youki、Gu Weilin、Dansako Hiromichi、Kim Hye-Sook、Yoshizaki Sayaka、Okumura Nobuaki、Ishikawa Tomohiro、Nishitsuji Hironori、Kato Fumihiro、Hishiki Takayuki、Satoh Shinya、Ishii Koji、Masuda Michiaki、Shimotohno Kunitada、Ikeda Masanori、Kato Nobuyuki
  • Journal Title: Biochemistry and Biophysics Reports Volume: 15 Pages: 1-6
  • DOI: 10.1016/j.bbrep.2018.05.007
  • Peer Reviewed / Open Access
• [Journal Article] Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response (2018)
  • Author(s): Imai Hirotaka、Dansako Hiromichi、Ueda Youki、Satoh Shinya、Kato Nobuyuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 504 Issue: 4 Pages: 672-678
  • DOI: 10.1016/j.bbrc.2018.08.195
  • Peer Reviewed
• [Journal Article] Regulation of interferon signaling and HCV-RNA replication by extracellular matrix. (2018)
  • Author(s): Kuwashiro T, Iwane S, Jinghe X, Matsuhashi S, Eguchi Y, Anzai K, Fujimoto K, Mizuta T, Sakamoto N, Ikeda M, Kato N, Ozaki I.
  • Journal Title: Int J Mol Med Volume: 42 Pages: 957-965
  • DOI: 10.3892/ijmm.2018.3693
  • Peer Reviewed
• [Journal Article] Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells. (2018)
  • Author(s): Murakami Y, Sugiyama K, Ebinuma H, Nakamoto N, Ojiro K, Chu PS, Taniki N, Saito Y, Teratani T, Koda Y, Suzuki T, Saito K, Fukasawa M, Ikeda M, Kato N, Kanai T, Saito H.
  • Journal Title: BMC Cancer. Volume: 3 Issue: 1 Pages: 680-680
  • DOI: 10.1186/s12885-018-4588-y
  • Peer Reviewed / Open Access
• [Journal Article] Ribavirin-induced down-regulation of CCAAT/enhancer-binding protein α leads to suppression of lipogenesis (2018)
  • Author(s): Satoh Shinya、Onomura Daichi、Ueda Youki、Dansako Hiromichi、Honda Masao、Kaneko Shuichi、Kato Nobuyuki
  • Journal Title: Biochemical Journal Volume: 476 Issue: 1 Pages: 137-149
  • DOI: 10.1042/bcj20180680
  • Peer Reviewed / Open Access
• [Journal Article] ULBP1 is induced by hepatitis C virus infection and is the target of the NK cell-mediated innate immune response in human hepatocytes (2018)
  • Author(s): Dansako Hiromichi、Imai Hirotaka、Ueda Youki、Satoh Shinya、Wakita Takaji、Kato Nobuyuki
  • Journal Title: FEBS Open Bio Volume: 8 Issue: 3 Pages: 361-371
  • DOI: 10.1002/2211-5463.12373
  • Peer Reviewed / Open Access
• [Journal Article] Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate-activated protein kinase-related kinases and retinoid X receptor α. (2017)
  • Author(s): S Satoh, K Mori, D Onomura, Y Ueda, H Dansako, M Honda, S Kaneko, M Ikeda, N Kato.
  • Journal Title: Hepatol Commun Volume: 1 Issue: 6 Pages: 550-563
  • DOI: 10.1002/hep4.1065
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of oncolytic adenovirus-mediated hepatotoxicity by liver-specific inhibition of NF-κB. (2017)
  • Author(s): Machitani M., Sakurai F., Wakabayashi K., Nakatani K., Tachibana M., Kato N., Fujiwara T., Mizuguchi H.
  • Journal Title: Mol. Ther. Oncolysis. Volume: 7 Pages: 76-85
  • DOI: 10.1016/j.omto.2017.10.003
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of preclinical antimalarial drugs, which can overcome direct-acting antivirals-resistant hepatitis C viruses, using the viral reporter assay systems. (2017)
  • Author(s): Ueda Y, Dansako H, Sato S, Kim HS, Wataya Y, Doi H, Ikeda M, Kato N.
  • Journal Title: Virus Res Volume: 235 Pages: 37-48
  • DOI: 10.1016/j.virusres.2017.03.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular mechanism underlying the suppression of CPB2 expression caused by persistent hepatitis C virus RNA replication. (2016)
  • Author(s): Sejima H, Satoh S, Dansako H, Honda M, Kaneko S, Ikeda M, Kato N.
  • Journal Title: Acta Med Okayama Volume: 70 Pages: 75-88
  • NAID: 120005749825
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of resistance-associated NS5A mutations in hepatitis C virus on viral production and susceptibility to antiviral reagents. (2016)
  • Author(s): Nitta S, Asahina Y, Matsuda M, Yamada N, Sugiyama R, Masaki T, Suzuki R, Kato N, Watanabe M, Wakita T, Kato T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34652-34652
  • DOI: 10.1038/srep34652
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rab13 is involved in the entry step of hepatitis C virus infection. (2016)
  • Author(s): Takeda M, Ikeda M, Satoh S, Dansako H, Wakita T, Kato N.
  • Journal Title: Acta Med Okayama Volume: 70 Pages: 111-118
  • NAID: 120005749829
  • Peer Reviewed
• [Presentation] 抗マラリア及び抗HCV薬候補N-89とN-251が有する幅広い抗ウイルス活性 (2018)
  • Author(s): 上田 優輝, 谷イ琳, 團迫 浩方, 金 惠淑, 吉崎 佐矢香, 奥村 暢章, 石川 知弘, 西辻 裕紀, 加藤 文博, 日紫喜 隆行, 佐藤 伸哉, 石井 孝司, 増田 道明, 下遠野 邦忠, 池田 正徳, 加藤 宣之
  • Organizer: 第28回抗ウイルス療法学会学術集会
• [Presentation] Suppression of oncolytic adenovirus-mediated hepatotoxicity by liver-specific inhibition of NF-κB (2018)
  • Author(s): Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Masashi Tachibana, Nobuyuki Kato, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会
• [Presentation] B型肝炎ウイルス感染ヒト不死化肝NKNT-3細胞由来のエクソソーム内タンパク質の解析 (2018)
  • Author(s): 團迫 浩方、今井 大誉、上田 優輝、佐藤 伸哉、加藤 宣之
  • Organizer: 第５回日本細胞外小胞学会
• [Presentation] Analysis of the new host factors necessary for susceptibility to HBV using plural human cell lines (2018)
  • Author(s): Youki Ueda, Hiromichi Dansako, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato
  • Organizer: 2018 International Meeting on Molecular Biology of Hepatitis B Virus
  • Int'l Joint Research
• [Presentation] Topoisomerase II inhibitor triggers cyclic GMP-AMP synthase-dependent innate immune response in human immortalized hepatocyte NKNT-3 (2018)
  • Author(s): Hirotaka Imai, Hiromichi Dansako, Youki Ueda, Shinya Satoh, Nobuyuki Kato
  • Organizer: 第66回日本ウイルス学会
• [Presentation] Drug screening for suppression of lipogenesis through downregulation of C/EBPα (2018)
  • Author(s): Shinya Satoh, Daichi Onomura, Koichi Watashi, Youki Ueda, Hiromichi Dansako, Masao Honda,, Shuichi Kaneko, Nobuyuki Kato
  • Organizer: 第66回日本ウイルス学会
• [Presentation] Mechanism of GPAM suppression by Anti-HCV drug ribavirin (2018)
  • Author(s): Daichi Onomura, Shinya Satoh, Youki Ueda, Hiromichi Dansako, Nobuyuki Kato
  • Organizer: 第66回日本ウイルス学会
• [Presentation] Screening of the new host factors necessary for HBV proliferation using plural human cell lines (2018)
  • Author(s): Youki Ueda, Hiromichi Dansako, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato
  • Organizer: 第66回日本ウイルス学会
• [Presentation] Analysis of host and viral factors contributing to resistant acquisition for the preclinical anti-HCV drugs, N-89 and N-251 (2018)
  • Author(s): Weilin Gu, Youki Ueda, Shinya Satoh, Hiromichi Dansako, Nobuyuki Kato
  • Organizer: 第66回日本ウイルス学会
• [Presentation] Highly expression of STING restricts HBV infection by mediating the induction of type III interferon in human immortalized hepatocyte NKNT-3 (2018)
  • Author(s): Hiromichi Dansako, Hirotaka Imai, Youki Ueda, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato
  • Organizer: 第66回日本ウイルス学会
• [Presentation] Perospirone, an antipsychotics, exhibits anti-hepatitis C virus activity (2018)
  • Author(s): Midori Takeda, Tomoka Taniguchi, Matsue Maezono, Takaji Wakita, Nobuyuki Kato, Masanori Ikeda
  • Organizer: 第66回日本ウイルス学会
• [Presentation] 抗HCV剤としての抗精神病薬ペロスピロンの可能性について (2018)
  • Author(s): 武田 緑、谷口 智香、前園 夏絵、脇田 隆字、加藤 宣之、池田 正徳
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] HCVポリメラーゼ/プロテアーゼ二重阻害活性を有するフラーレン誘導体の細胞内HCV複製阻害及び酸化ストレス抑制効果 (2017)
  • Author(s): 片岡 裕樹、上田 優輝、髙橋 恭子、中村 成夫、大江 知之、 加藤 宣之、増野 匡彦
  • Organizer: 日本薬学会第137年会
• [Presentation] クロファラビンはドラッグリポジショニングにより見いだされた 抗HBV活性と抗HCV活性を有する治療剤候補である (2017)
  • Author(s): 武田 緑、加藤 宣之、池田 正徳
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] Development of human hepatoma cell line, Li23-derived cells possessing high susceptibility to HBV (2017)
  • Author(s): Youki Ueda, Hiromichi Dansako, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato
  • Organizer: 2017 International Meeting on Molecular Biology of Hepatitis B Virus
  • Int'l Joint Research
• [Presentation] Downregulation of C/EBPα by anti-HCV drug ribavirin leads to the suppression of triglyceride synthesis pathway (2017)
  • Author(s): Shinya Satoh, Daichi Onomura, Youki Ueda, Hiromichi Dansako, Masao Honda, Shuichi Kaneko, Nobuyuki Kato
  • Organizer: 第65回日本ウイルス学会
• [Presentation] Identification of new amino acid substitutions contributing to DAA-resistance, using HCV reporter assay systems (2017)
  • Author(s): Youki Ueda, Hiromichi Dansako, Shinya Satoh, Masanori Ikeda, Nobuyuki Kato
  • Organizer: 第65回日本ウイルス学会
• [Presentation] Resistant acquisition mechanism for anti-HCV drug candidates, N-89 and its derivative N-251 (2017)
  • Author(s): Weilin Gu, Youki Ueda, Shinya Satoh, Hiromichi Dansako, Nobuyuki Kato
  • Organizer: 第65回日本ウイルス学会
• [Presentation] 交感神経遮断薬であるグアンファシンは抗HCV活性を示す (2017)
  • Author(s): 武田 緑、前園 夏絵、上高原 美奈、脇田 隆字、加藤 宣之、 池田 正徳
  • Organizer: 第65回日本ウイルス学会
• [Presentation] Development of HBV infection system using human immortalized hepatocyte NKNT-3 cells (2017)
  • Author(s): Hiromichi Dansako, Hirotaka Imai, Youki Ueda, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato
  • Organizer: 第65回日本ウイルス学会
• [Presentation] Both host and viral factors contribute to the resistance to preclinical anti-HCV drugs, N-89 and N-251. (2016)
  • Author(s): Gu W, Ueda Y, Dansako H, Satoh S, Kato N.
  • Organizer: The 64th Annual Meeting of The Japanese Society for Virology
  • Place of Presentation: 札幌コンベンションセンター、札幌
  • Year and Date: 2016-10-23
• [Presentation] Genetic characterization of HCVs obtained from HCV-RNA-replicating cells possessing a DAA-, N-89-, or N-251-resistant phenotype. (2016)
  • Author(s): Ueda Y, Dansako H, Satoh S, Ikeda M, Kato N.
  • Organizer: The 64th Annual Meeting of The Japanese Society for Virology
  • Place of Presentation: 札幌コンベンションセンター、札幌
  • Year and Date: 2016-10-23
• [Presentation] DNA-PKcs and Rad18 are required for HCV replication. (2016)
  • Author(s): Ariumi Y, Tateishi S, Wakita T, Kato N.
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: 国際会議場、京都
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] HBVとHCVに対する抗ウイルス剤の探索 (2016)
  • Author(s): 武田 緑、團迫 浩方、馬場 昌範、加藤 宣之、池田 正徳
  • Organizer: 第53回日本ウイルス学会九州支部会
  • Place of Presentation: 宮崎市民プラザ、宮崎
  • Year and Date: 2016-09-01
• [Presentation] DAA製剤によるHCV治療におけるN-89/N-251の有用性とそれらの作用機序の解析 (2016)
  • Author(s): 上田 優輝、團迫 浩方、佐藤 伸哉、池田 正徳、加藤 宣之
  • Organizer: 第26回抗ウイルス療法学会総会
  • Place of Presentation: 名古屋市立大学、名古屋
  • Year and Date: 2016-05-13
• [Remarks] 腫瘍ウイルス学分野Research
  • URL: http://www.okayama-u.ac.jp/user/med/dmb/research.html