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Elucidation of synergy in hepatocarcinogenesis by hepatitis B virus, inflammation and hypernutrition

Research Project

Project/Area Number 15H04807
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

KOIKE KAZUHIKO  東京大学, 医学部附属病院, 教授 (80240703)

Co-Investigator(Kenkyū-buntansha) 森屋 恭爾  東京大学, 医学部附属病院, 教授 (00272550)
堤 武也  東京大学, 医科学研究所, 准教授 (00726739)
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
Keywords肝癌 / B型肝炎 / 炎症 / ウイルス / 肥満 / 内科 / 肝発癌 / NASH / 脂肪肝
Outline of Final Research Achievements

Hepatitis B virus (HBV) infection can lead to cirrhosis and hepatocellular carcinoma. Episomal viral covalently closed circular DNA (cccDNA) minichromosomes and transcripts from cccDNA continue to be expressed over the long term. We showed that the host protein DExH-box helicase 9 (DXH9) is associated with viral RNAs. We also showed that viral-derived circular RNA is produced during HBV replication, and the amount is increased by knockdown of the DHX9 protein, which, in turn, results in decreased viral protein levels but does not affect the levels of HBV DNA. In addition, through a comprehensive compound screen using a newly constructed split luciferase system, we showed that nitazoxanide (NTZ) efficiently inhibits the HBx-DDB1 interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system, in in vitro HBV replicating models, and in human primary hepatocytes naturally infected with HBV.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (32 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (5 results) Journal Article (17 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 17 results,  Open Access: 17 results,  Acknowledgement Compliant: 5 results) Presentation (10 results) (of which Int'l Joint Research: 4 results,  Invited: 8 results)

  • [Int'l Joint Research] Icahn School of Medicine at Mount Sinai(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] National University Health System(Singapore)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Xiamen University, Xiamen, Fujian(China)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] The Scripps Research Institute(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] The University of Texas Medical School(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] DHX9 regulates production of hepatitis B virus-derived circular RNA and viral protein levels2018

    • Author(s)
      Sekiba K, Otsuka M, Ohno M, Kishikawa T, Yamagami M, Suzuki T, Ishibashi R, Seimiya T, Tanaka E, Koike K.
    • Journal Title

      Oncotarget

      Volume: 9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Relationship of muscle cramps to quality of life and sleep disturbance in patients with chronic liver diseases: a nationwide study2018

    • Author(s)
      Iwasa Motoh、Karino Yoshiyasu、Kawaguchi Takumi、Nakanishi Hiroyuki、Miyaaki Hisamitsu、Shiraki Makoto、Nakajima Tomoaki、Sawada Yasuhiko、Yoshiji Hitoshi、Okita Kiwamu、Koike Kazuhiko
    • Journal Title

      Liver International

      Volume: 38 Issue: 12 Pages: 2309-2316

    • DOI

      10.1111/liv.13745

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity2018

    • Author(s)
      Fujiwara Naoto、Nakagawa Hayato、Enooku Kenichiro、Otsuka Motoyuki、Tateishi Keisuke、Koike Kazuhiko
    • Journal Title

      Gut

      Volume: 67 Issue: 8 Pages: 1493-1504

    • DOI

      10.1136/gutjnl-2017-315193

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Response criteria of tolvaptan for the treatment of hepatic edema2017

    • Author(s)
      Hiramine Yasunari、Uojima Haruki、Nakanishi Hiroyuki、Hiramatsu Akira、Iwamoto Takuya、Kimura Mutsuumi、Kawaratani Hideto、Terai Shuji、Yoshiji Hitoshi、Uto Hirofumi、Sakaida Isao、Izumi Namiki、Okita Kiwamu、Koike Kazuhiko
    • Journal Title

      Journal of Gastroenterology

      Volume: 53 Issue: 2 Pages: 258-268

    • DOI

      10.1007/s00535-017-1366-6

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] RASAL1 is a potent regulator of hepatic stellate cell activity and liver fibrosis2017

    • Author(s)
      Takata Akemi、Otsuka Motoyuki、Kishikawa Takahiro、Yamagami Mari、Ishibashi Rei、Sekiba Kazuma、Suzuki Tatsunori、Ohno Motoko、Yamashita Yui、Abe Takaya、Masuzaki Ryota、Ikenoue Tsuneo、Koike Kazuhiko
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 39 Pages: 64840-64852

    • DOI

      10.18632/oncotarget.17609

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Randomized prospective study showing the non-inferiority of tenofovir to entecavir in treatment-na?ve chronic hepatitis B patients2017

    • Author(s)
      Koike Kazuhiko、Suyama Kazuaki、Ito Hiroshi、Itoh Hiroshi、Sugiura Wataru
    • Journal Title

      Hepatology Research

      Volume: 48 Issue: 1 Pages: 59-68

    • DOI

      10.1111/hepr.12902

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mortality and hemorrhagic complications associated with radiofrequency ablation for treatment of hepatocellular carcinoma in patients on hemodialysis for end-stage renal disease: A nationwide survey.2017

    • Author(s)
      Sato M, Tateishi R, Yasunaga H, Matsui H, Horiguchi H, Fushimi K, Koike K.
    • Journal Title

      J Gastroenterol Hepatol.

      Volume: 32 Issue: 11 Pages: 1873-1878

    • DOI

      10.1111/jgh.13780

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands.2017

    • Author(s)
      Nakagawa H, Suzuki N, Hirata Y, Hikiba Y, Hayakawa Y, Kinoshita H, Ihara S, Uchino K, Nishikawa Y, Ijichi H, Otsuka M, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Tateishi K, Koike K.
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 114(19) Issue: 19

    • DOI

      10.1073/pnas.1619416114

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system2017

    • Author(s)
      Sekiba K, Yamagami M, Otsuka M, Suzuki T, Kishikawa T, Ishibashi R, Ohno M, Sato M, Koike K
    • Journal Title

      Biochem Biophys Res Commun

      Volume: - Issue: 2 Pages: 521-525

    • DOI

      10.1016/j.bbrc.2017.03.076

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells2016

    • Author(s)
      Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, Karin M
    • Journal Title

      Cancer Cell

      Volume: 29 Issue: 6 Pages: 935-948

    • DOI

      10.1016/j.ccell.2016.04.006

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutual antagonism between hepatitis B viral mRNA and host microRNA let-7.2016

    • Author(s)
      Takata A, Otsuka M, Ohno M, Kishikawa T, Yoshikawa T, Koike K.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 23237-23237

    • DOI

      10.1038/srep23237

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] The intrahepatic expression levels of bile acid transporters are inversely correlated with the histological progression of nonalcoholic fatty liver disease2016

    • Author(s)
      Okushin K, Tsutsumi T, Enooku K, Fujinaga H, Kado A, Shibahara J, Fukayama M, Moriya K, Yotsuyanagi H, Koike K
    • Journal Title

      J Gastroenterol

      Volume: 51 Issue: 8 Pages: 808-818

    • DOI

      10.1007/s00535-015-1148-y

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels.2016

    • Author(s)
      Enooku K, Uranbileg B, Ikeda H, Kurano M, Sato M, Kudo H, Maki H, Koike K, Hasegawa K, Kokudo N, Yatomi Y.
    • Journal Title

      PLoS One

      Volume: 11 Issue: 9 Pages: e0161825-e0161825

    • DOI

      10.1371/journal.pone.0161825

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sarcopenia, Intramuscular Fat Deposition, and Visceral Adiposity Independently Predict the Outcomes of Hepatocellular Carcinoma2015

    • Author(s)
      Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, Nakagomi R, Kondo M, Nakatsuka T, Minami T, Sato M, Uchino K, Enooku K, Kondo Y, Asaoka Y, Tanaka Y, Ohtomo K, Shiina S, Koike K
    • Journal Title

      J Hepatol

      Volume: 62 Issue: 1 Pages: 131-140

    • DOI

      10.1016/j.jhep.2015.02.031

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine2015

    • Author(s)
      Kishikawa T, Otsuka M, Tan PS, Ohno M, Sun X, Yoshikawa T, Shibata C, Takata A, Kojima K, Takehana K, Ohishi M, Ota S, Noyama T, Kondo Y, Sato M, Soga T, Hoshida Y, Koike K
    • Journal Title

      Oncotarget

      Volume: 6 Pages: 8339-8352

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression2015

    • Author(s)
      Yoshikawa, T. Wu, J. Otsuka, M. Kishikawa, T. Ohno, M. Shibata, C. Takata, A. Han, F. Kang, Y. J. Chen, C. A. Shyu, A. B. Han, J. Koike, K
    • Journal Title

      Nucleic Acids Res

      Volume: 43(15) Issue: 15 Pages: 7577-89

    • DOI

      10.1093/nar/gkv728

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences.2015

    • Author(s)
      Watanabe Y, Yamamoto H, Oikawa R, Toyota M, Yamamoto M, Kokudo N, Tanaka S, Arii S, Yotsuyanagi H, Koike K, Itoh F.
    • Journal Title

      Genome Research

      Volume: 25(3) Issue: 3 Pages: 328-337

    • DOI

      10.1101/gr.175240.114

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] NASH・肥満関連肝癌における特異的代謝異常に着目した発癌促進機構解明2017

    • Author(s)
      藤原直人、中川勇人、小池和彦
    • Organizer
      第53回日本肝臓学会総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] HBV mRNAと宿主microRNA let-7の相互作用2016

    • Author(s)
      小池和彦
    • Organizer
      犬山シンポジウム
    • Place of Presentation
      名鉄犬山ホテル
    • Year and Date
      2016-08-04
    • Related Report
      2016 Annual Research Report
  • [Presentation] 糖尿病・代謝と肝臓2016

    • Author(s)
      小池和彦
    • Organizer
      第29回肝臓フォーラム(東部)
    • Place of Presentation
      経団連会館
    • Year and Date
      2016-07-09
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 肝炎2016

    • Author(s)
      小池和彦
    • Organizer
      日本医学会公開フォーラム
    • Place of Presentation
      日本医師会館
    • Year and Date
      2016-06-18
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Impact of demographic changes on Internal Medicine2016

    • Author(s)
      Kazuhiko Koike
    • Organizer
      122th DGIM(ドイツ内科学会)
    • Place of Presentation
      Mannheim Congress Center Rosengarten
    • Year and Date
      2016-04-11
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Body composition and prognosis of hepatocellular carcinoma2016

    • Author(s)
      Koike K
    • Organizer
      35thUS-Japan Cooperative Medical Sciences Program (USJCMSP) Meeting
    • Place of Presentation
      North Bethesda, MD, USA
    • Year and Date
      2016-01-13
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] MicroRNA and HBV pathogenesis2015

    • Author(s)
      Koike K
    • Organizer
      3rd Italy-Japan Liver Work Shop
    • Place of Presentation
      Napoli University, Italy
    • Year and Date
      2015-10-26
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 50 years of hepatology in Japan: Past, Present and Future2015

    • Author(s)
      Koike K
    • Organizer
      20th Korean Association of the Study of the Liver
    • Place of Presentation
      Busan, Korea
    • Year and Date
      2015-09-11
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 肝疾患と体質:我が国の肝臓病の現状2015

    • Author(s)
      小池和彦
    • Organizer
      第65回日本体質医学会
    • Place of Presentation
      札幌コンベンションセンター(北海道・札幌市)
    • Year and Date
      2015-07-04
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] MicroRNAと肝臓2015

    • Author(s)
      小池和彦
    • Organizer
      肝細胞研究会
    • Place of Presentation
      米子コンベンションセンター(鳥取県・米子市)
    • Year and Date
      2015-06-05
    • Related Report
      2015 Annual Research Report
    • Invited

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Published: 2015-04-16   Modified: 2022-10-07  

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