Research on host factors which are involved in the progression of HCV-induced hepatic deseases

• Project/Area Number: 25293110
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• 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): IKEDA Masanori 鹿児島大学, 大学院医歯(薬)学総合研究科, 教授 (30315767) ; DANSAKO Hiromichi 岡山大学, 医歯(薬)学総合研究科, 助教 (80379841) ; SATOH Shinya 岡山大学, 医歯(薬)学総合研究科, 助教 (80333558)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: C型肝炎ウイルス / 長期継代培養 / 遺伝子発現変動 / miRNA発現変動 / Exosome / ヒト不死化肝細胞 / RNA複製増殖 / マイクロアレイ解析

Outline of Final Research Achievements

We studied to clarify the relation of long-term replication of HCV RNA and hepatocarcinogenesis, and then obtained the following results. (1) Regarding CPB2 and BASP1 genes, whose expression levels were remarkably suppressed by long-term replication of HCV RNA, we analyzed the molecular mechanism of the gene suppression, and partly elucidated it. (2) We found that miR-22 and miR-34a were significantly suppressed by long-term replication of HCV RNA. (3) We developed the reproducible and stable method that we could prepare exosome derived from human hepatocytes, and then we applied this method to the variability analysis of exosome in the long-term culture of HCV RNA-replicating cells. (4) Using immortalized human hepatocytes, we tried the development of a new model of HCV RNA-replicating cells, and then obtained the useful knowledge for future study.

Research Products

• [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] 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
• [Journal Article] Annexin A1 negatively regulates viral RNA replication of hepatitis C virus. (2015)
  • Author(s): Hiramoto H, Dansako H, Takeda M, Satoh S, Wakita T, Ikeda M, Kato N.
  • Journal Title: Acta Med Okayama Volume: 69 Pages: 71-78
  • NAID: 120005595787
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Control of HCV Replication with iMIRs, a Novel Anti-RNAi Agent (2015)
  • Author(s): Saori Itami, Yutaka Eguchi, Takayuki Mizutani, Eriko Aoki, Tadaaki Ohgi, Masahiko Kuroda, Takahiro Ochiya, Nobuyuki Kato, Hiroshi I Suzuki, Norifumi Kawada and Yoshiki Murakami
  • Journal Title: Molecular Therapy Nucleic Acids Volume: 4 Pages: e219-e219
  • DOI: 10.1038/mtna.2014.71
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of FKBP6 in hepatitis C virus replication. (2015)
  • Author(s): Kasai H, Kawakami Y, Yokoe H, Yoshimura K, Matsuda M, Yasumoto J, Maekawa S, Yamashita A, Tanaka T, Ikeda M, Kato N, Okamoto T, Matsuura Y, Sakamoto N, Enomoto N, Takeda S, Fujii H, Tsubuki M, Kusunoki M, Moriishi K.
  • Journal Title: Scientific reports Volume: 5 Issue: 1 Pages: 16699-16699
  • DOI: 10.1038/srep16699
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Establishment of hepatitis C virus RNA-replicating cell lines possessing ribavirin-resistant phenotypes (2015)
  • Author(s): Satoh S, Mori K, Ueda Y, Sejima H, Dansako H, Ikeda M, Kato N.
  • Journal Title: PLoS ONE Volume: 10 Issue: 2 Pages: e0118313-e0118313
  • DOI: 10.1371/journal.pone.0118313
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-HCV activity of the Chinese medicinal fungus Cordyceps militaris. (2014)
  • Author(s): Ueda Y, Mori K, Satoh S, Dansako H, Ikeda M, Kato N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 447 Issue: 2 Pages: 341-5
  • DOI: 10.1016/j.bbrc.2014.03.150
  • Peer Reviewed
• [Journal Article] Rab18 is required for viral assembly of hepatitis C virus through trafficking of the core protein to lipid droplets. (2014)
  • Author(s): Dansako H, Hiramoto H, Ikeda M, Wakita T, Kato N.
  • Journal Title: Virology Volume: 462-463 Pages: 166-74
  • DOI: 10.1016/j.virol.2014.05.017
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis and inhibitory activity on hepatitis C virus RNA replication of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)aniline analogs (2014)
  • Author(s): Matsuno K, Ueda Y, Fukuda M, Onoda K, Waki M, Ikeda M, Kato N, Miyachi H.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 24 Issue: 17 Pages: 4276-80
  • DOI: 10.1016/j.bmcl.2014.07.019
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Alternative endocytosis pathway for productive entry of hepatitis C virus. (2014)
  • Author(s): Matsuda M, Suzuki R, Kataoka C, Watashi K, Aizaki H, Kato N, Matsuura Y, Suzuki T, Wakita T
  • Journal Title: J Gen Virol. Volume: 95(Pt 12) Issue: 12 Pages: 2658-67
  • DOI: 10.1099/vir.0.068528-0
  • Peer Reviewed / Open Access
• [Journal Article] Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization. (2014)
  • Author(s): Hara Y, Yanatori I, Ikeda M, Kiyokage E, Nishina S, Tomiyama Y, Toida K, Kishi F, Kato N, Imamura M, Chayama K, Hino K.
  • Journal Title: Am J Pathol. 2014 Volume: 184 Issue: 11 Pages: 3026-39
  • DOI: 10.1016/j.ajpath.2014.07.024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis of 3',4'-difluoro-3'-deoxyribonucleosides and its evaluation of the biological activities: Discovery of a novel type of anti-HCV agent 3',4'-difluorocordycepin (2014)
  • Author(s): Shimada H, Haraguchi K, Hotta K, Miyaike T, Kitagawa Y, Tanaka H, Kaneda R, Abe H, Shuto S, Mori K, Ueda Y, Kato N, Snoeck R, Andrei G, Balzarini J.
  • Journal Title: Bioorg. Med. Chem. Volume: 22 Issue: 21 Pages: 6174-82
  • DOI: 10.1016/j.bmc.2014.08.024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C. (2014)
  • Author(s): Maekawa S, Enomoto N
  • Journal Title: J Gastroenterol. Volume: 49(1) Issue: 12 Pages: 163-164
  • DOI: 10.1371/journal.pone.0082299
  • Peer Reviewed
• [Journal Article] IPS-1 is essential for type III interferon production by hepatocytes and dendritic cells in response to hepatitis C virus infection. (2014)
  • Author(s): Okamoto M, Oshiumi H, Azuma M, Kato N, Matsumoto M, Seya T.
  • Journal Title: J. Immunol. Volume: 192 Pages: 2770-2777
  • Peer Reviewed
• [Journal Article] Genetic Characterization of Hepatitis C Virus in Long-Term RNA Replication Using Li23 Cell Culture Systems. (2014)
  • Author(s): Kato N, Sejima H, Ueda Y, Mori K, Satoh S, Dansako H, Ikeda M.
  • Journal Title: PLoS One Volume: 9 Issue: 3 Pages: e91156-e91156
  • DOI: 10.1371/journal.pone.0091156
  • NAID: 120005697276
  • Peer Reviewed / Open Access
• [Journal Article] Hepatitis C virus NS4B targets lipid droplets through hydrophobic residues in the amphipathic helices (2013)
  • Author(s): Tanaka T et al.
  • Journal Title: J Lipid Res. Volume: 54(4) Issue: 4 Pages: 881-892
  • DOI: 10.1194/jlr.m026443
  • Peer Reviewed
• [Journal Article] Class A scavenger receptor 1 (MSR1) restricts hepatitis C virus replication by mediating toll-like receptor 3 recognition of viral RNAs produced in neighboring cells. (2013)
  • Author(s): Dansako H, Yamane D, Welsch C, McGivern DR, Hu F, Kato N, and Lemon SM.
  • Journal Title: PLoS Pathogens Volume: 9 Issue: 5 Pages: e1003345-e1003345
  • DOI: 10.1371/journal.ppat.1003345
  • Peer Reviewed
• [Journal Article] Adenosine kinase is a key determinant for the anti-HCV activity of ribavirin (2013)
  • Author(s): Mori K, Hiraoka O, Ikeda M, Ariumi Y, Hiramoto A, Wataya Y, Kato N
  • Journal Title: Hepatology Volume: 58 Issue: 4 Pages: 1236-44
  • DOI: 10.1002/hep.26421
  • Peer Reviewed
• [Journal Article] Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy. (2013)
  • Author(s): Shinohara Y, Imajo K, Yoneda M, Tomeno W, Ogawa Y, Kirikoshi H, Funakoshi K, Ikeda M, Kato N, Nakajima A, Saito S.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 432 Issue: 2 Pages: 326-332
  • DOI: 10.1016/j.bbrc.2013.01.103
  • Peer Reviewed
• [Journal Article] Ca(2+) /S100 proteins regulate HCV virus NS5A-FKBP8/FKBP38 interaction and HCV virus RNA replication (2013)
  • Author(s): Tani J, Shimamoto S, Mori K, Kato N, Moriishi K, Matsuura Y, Tokumitsu H, Tsuchiya M, Fujimoto T, Kato K, Miyoshi H, Masaki T, Kobayashi R.
  • Journal Title: Liver Int Volume: 33 Issue: 7 Pages: 1008-1018
  • DOI: 10.1111/liv.12151
  • Peer Reviewed
• [Journal Article] Direct targeting of proteins to lipid droplets demonstrated by time-lapse live cell imaging. (2013)
  • Author(s): Tanaka T, Kuroda K, Ikeda M, Kato N, Shimizu K, Makishima M.
  • Journal Title: J Biosci. Bioeng. Volume: 116 Pages: 620-623
  • NAID: 110009685215
  • Peer Reviewed
• [Journal Article] Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity. (2013)
  • Author(s): Ding Q, Cao X, Lu J, Huang B, Liu YJ, Kato N, Shu HB, Zhong J.
  • Journal Title: J Hepatol. Volume: 59 Issue: 1 Pages: 52-58
  • DOI: 10.1016/j.jhep.2013.03.019
  • Peer Reviewed
• [Journal Article] Hepatic triglyceride lipaseplays an essential role in changing the lipid metabolism in genotype 1b hepatitis C virus replicon cells and hepatitis C patients (2013)
  • Author(s): ShinoharaY, Imajo K, Yoned M, Tomeno W, Ogawa Y, Fujita K, Kirikoshi H, Takahashi J, Funakoshi K, Ikeda M, Kato N, Nakajima A, Saito S
  • Journal Title: Hepatol Res Volume: 43 Issue: 11 Pages: 1190-1198
  • DOI: 10.1111/hepr.12072
  • Peer Reviewed
• [Journal Article] Suppressive Effect of the Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), on Hepatitis C Virus Replication via Epigenetic Changes in Host Cells (2013)
  • Author(s): Sato, A., Saito, Y., Sugiyama, K., Sakasegawa, N., Muramatsu, T., Fukuda, S., Yoneya, M., Kimura, M., Ebinuma, H., Hibi, T., Saito, H
  • Journal Title: J Cell Biochem Volume: 印刷中 Issue: 9 Pages: 1987-1996
  • DOI: 10.1002/jcb.24541
  • Peer Reviewed
• [Journal Article] New preclinical antimalarial drugs potently inhibit hepatitis C virus genotype 1b RNA replication (2013)
  • Author(s): Ueda Y, et al.
  • Journal Title: PLoS ONE Volume: 8 Issue: 8 Pages: e72519-e72519
  • DOI: 10.1371/journal.pone.0072519
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication. (2013)
  • Author(s): Ban S, Ueda Y, Ohashi M, Matsuno K, Ikeda M, Kato N, and Miyachi H.
  • Journal Title: Bioorg. Med. Chem. Letters Volume: 23 Pages: 4774-4778
  • Peer Reviewed
• [Presentation] C型肝炎ウイルスの阻害剤探索を目的にしたスクリーニングシステムの開発 (2015)
  • Author(s): 武田 緑、池田 正徳、佐藤 伸哉、團迫 浩方、加藤 宣之.
  • Organizer: 第38回日本分子生物学会年会 第88回に本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド、神戸
  • Year and Date: 2015-12-01
• [Presentation] Function and transcriptional regulation mechanism of CPB2 gene downregulated by persistent HCV RNA replication. (2015)
  • Author(s): 瀬島 寛恵、佐藤 伸哉、團迫 浩方、上田 優輝、本多 政夫、金子 周一、池田 正徳、加藤 宣之
  • Organizer: 第6３回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2015-11-22
• [Presentation] Improved ExoQuick protocol for the preparation of exosomes released from human heptoma cells. (2015)
  • Author(s): Hiroki Hiramoto, Hiromichi Dansako, Youki Ueda, Shinya Satoh, Masanori Ikeda, Nobuyuki Kato.
  • Organizer: 第6３回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2015-11-22
• [Presentation] DNA repair protein Rad18 is required for HCV replication. (2015)
  • Author(s): Yasuo Ariumi, Mariko Yasuda-Inoue, Satoshi Tateishi, Takaji Wakita, Nobuyuki Kato.
  • Organizer: 第6３回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2015-11-22
• [Presentation] New function of anti-HCV drug ribavirin: suppressive effect in hepatic lipogenesis. (2015)
  • Author(s): Shinya Satoh, Youki Ueda, Hiromichi Dansako, Masao Honda, Shuichi Kaneko, Masanori Ikeda, Nobuyuki Kato.
  • Organizer: 第6３回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2015-11-22
• [Presentation] Antimalarial preclinical drugs, N-89 and N-251, overcome various DAAs-resistant HCVs. (2015)
  • Author(s): Youki Ueda, Hiromichi Dansako, Shinya Satoh, Hye-Sook Kim, Hiroyuki Doi, Yusuke Wataya, Masanori Ikeda, Nobuyuki Kato.
  • Organizer: 第6３回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2015-11-22
• [Presentation] HCVライフサイクルにおける小胞輸送蛋白質Rab13の役割 (2014)
  • Author(s): 武田 緑、池田 正徳、佐藤 伸哉、團迫 浩方、脇田 隆字、加藤 宣之
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] 長期にわたるHCV-RNA複製によるBASP1とCPB2遺伝子の発現低下の分子機構の解析 (2014)
  • Author(s): 瀬島 寛恵、佐藤 伸哉、團迫 浩方、池田 正徳、加藤 宣之
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] HCV-RNAの長期複製によって発現低下したBASP1とCPB2遺伝子の発現制御機構の解析 (2014)
  • Author(s): 瀬島 寛恵、佐藤 伸哉、團迫 浩方、池田 正徳、加藤 宣之
  • Organizer: 第18回日本肝臓学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2014-10-23 – 2014-10-24
• [Presentation] C型肝炎ウイルスRNAの長期細胞内複製によって発現低下した遺伝子の発現制御機構の解析 (2014)
  • Author(s): 瀬島 寛恵 佐藤 伸哉 團迫 浩方 池田 正徳 加藤 宣之
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Human hepatoma HuH-7 cell line-derived RSc cells show higher viral productivity in response to infection with HCV-JFH-1 than Huh7.5 cells. (2014)
  • Author(s): Dansako H, Hiramoto H, Ikeda M, Wakita T, Kato N.
  • Organizer: 21th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Characterization of anti-HCV activity of N-251, a preclinical antimalarial drug, and its combination effect with DAA (2014)
  • Author(s): Ueda Y, Kim HS, Dansako H, Satoh S, Ikeda M, Doi H, Wataya Y, Kato N
  • Organizer: 21th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Analysis on transcriptional regulatory mechanisms of genes whose expressions were reduced during long-term intracellular HCV-RNA replication (2014)
  • Author(s): Sejima H, Satoh S, Dansako H, Ikeda M, Kato N
  • Organizer: 21th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Annexin A1 negatively regulates HCV RNA replication (2014)
  • Author(s): Hiramoto H, Dansako H, Takeda M, Satoh S, Wakita T, Ikeda M, Kato N
  • Organizer: 21th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] DDX21 RNA helicase restricts HCV infection (2014)
  • Author(s): Ariumi Y, Kuroki M, Siddiqui R, Hijikata M, Ikeda M, Wakita T, Kato N
  • Organizer: 21th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Rab13 is an essential host factor for HCV entry (2014)
  • Author(s): Tekeda M, Ikeda M, Satoh S, Dansako H, Wakita T, Kato N
  • Organizer: 21th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Banff, Canada
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Identification of microRNAs showing differential expression profiles in cell-based HCV RNA replication for 2 years. (2013)
  • Author(s): 瀬島 寛恵、森 京子、佐藤 伸哉、團迫 浩方、池田 正徳、加藤 宣之.
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Identification of two microRNAs showing decreased expression in cell-based HCV RNA replication for 2 years. (2013)
  • Author(s): Hiroe Sejima, Kyoko Mori, Shinya Satoh, Hiromichi Dansako, Masanori Ikeda, Nobuyuki Kato.
  • Organizer: 20th International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Melbourne Convention and Exhibition Centre (Australia)
• [Presentation] Rab18 is required for viral assembly of hepatitis C virus through the association with core protein around lipid droplet. (2013)
  • Author(s): Hiromichi Dansako, Hiroki Hiramoto, Masanori Ikeda, Takaji Wakita, Nobuyuki Kato.
  • Organizer: 20th International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Melbourne Convention and Exhibition Centre (Australia)
• [Presentation] C型肝炎ウイルスのゲノム複製が2年間にわたることで発現レベルが変動したマイクロRNAの同定. (2013)
  • Author(s): 瀬島 寛恵、森 京子、佐藤 伸哉、團迫 浩方、池田 正徳、加藤 宣之.
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] C型肝炎ウイルスのライフサイクルにおける宿主因子annexin A1の役割. (2013)
  • Author(s): 平本 洸貴, 團迫 浩方, 瀬島 寛恵, 森 京子, 佐藤 伸哉, 池田 正徳, 脇田 隆字, 加藤 宣之.
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Rab18はC型肝炎ウイルスの感染性粒子形成に重要な宿主因子である. (2013)
  • Author(s): 團迫 浩方、平本 洸貴、池田 正徳、脇田 隆字、加藤 宣之.
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Ｃ型肝炎ウイルスNS4Bの両親媒性へリックス内疎水性残基がウイルス複製に果たす役割. (2013)
  • Author(s): 田中 寅彦、山本 真民、黒田 和道、脇田 隆字、池田 正徳、加藤 宣之、槇島 誠.
  • Organizer: 第６１回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場