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Functional analysis of MICA in hepatitis C virus-induced hepatocellular carcinoma and its therapeutic application

Research Project

Project/Area Number 24390184
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

KATO NAOYA  東京大学, 医科学研究所, 准教授 (90313220)

Co-Investigator(Renkei-kenkyūsha) 室山 良介  
後藤 覚  
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2012: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Keywords肝癌 / C型肝炎ウイルス / MICA / ゲノムワイド関連解析 / SNP / 薬剤スクリーニング / SAHA / プロモーター / microRNA / ncRNA
Outline of Final Research Achievements

We identified the association between hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) and MICA single nucleotide polymorphism (SNP) by a genome wide association study (GWAS). Thus, we have aimed to analyze the function of MICA in HCV-induced HCC and to establish the way to prevent hepatocarcinogenesis through regulating MICA expression. First, the MICA SNP to regulate individual differences in MICA expression was examined, and two responsible SNPs were identified in the promoter region of MICA. Next, the drug to upregulate MICA was screened using HCC cells stably transfected by the reporter having MICA promoter region in its upstream and U.S. Food and Drug Administration (FDA)-approved drug library. SAHA most strongly upregulated MICA. Moreover, SAHA augmented NK cell cytotoxicity against HCC cells through upregulating MICA. Thus, SAHA could be the attractive option to treat HCV-induced HCC.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report

Research Products

(32 results)

All 2015 2014 2013 2012

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Acknowledgement Compliant: 4 results,  Open Access: 2 results) Presentation (22 results)

  • [Journal Article] MICA SNPs and the NKG2D system in virus-induced HCC.2015

    • Author(s)
      Goto K, Kato N.
    • Journal Title

      J Gastroenterol

      Volume: 50 Pages: 261-272

    • DOI

      10.1007/s00535-014-1000-9

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The characteristic changes in hepatitis B virus X region for hepatocellular carcinoma: A comprehensive analysis based on global data.2015

    • Author(s)
      Li W, Goto K, Matsubara Y, Ito S, Murayama R, Li Q, Kato N.
    • Journal Title

      PLoS One

      Volume: in press

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection2014

    • Author(s)
      Sato M, Kato N, Tateishi R, Muroyama R, Kowatari N, Li W, Goto K, Otsuka M, Shiina S, Yoshida H, Omata M, Koike K
    • Journal Title

      Journal of Gastroenterology

      Volume: 49(4) Pages: 748-54

    • DOI

      10.1007/s00535-013-0826-x

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels.2014

    • Author(s)
      Shibata C, Ohno M, Otsuka M, Kishikawa T, Goto K, Muroyama R, Kato N, Yoshikawa T, Takata A, Koike K.
    • Journal Title

      Virology.

      Volume: 462-463 Pages: 42-48

    • DOI

      10.1016/j.virol.2014.05.024

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Specific delivery of microRNA93 into HBV-replicating hepatocytes downregulates protein expression of liver cancer susceptible gene MICA.2014

    • Author(s)
      Ohno M, Otsuka M, Kishikawa T, Shibata C, Yoshikawa T, Takata A, Muroyama R, Kowatari N, Sato M, Kato N, Kuroda S, Koike K.
    • Journal Title

      Oncotarget

      Volume: 5 Pages: 5581-5590

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of IL28B Genetic Variation on HCV-Induced Liver Fibrosis, Inflammation, and Steatosis: A Meta-Analysis.2014

    • Author(s)
      Sato M, Kondo M, Tateishi R, Fujiwara N, Kato N, Yoshida H, Taguri M, Koike K
    • Journal Title

      PLoS One

      Volume: 9

    • DOI

      10.1371/journal.pone.0091822

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of PNPLA3 polymorphisms on the development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection.2014

    • Author(s)
      Sato M, Kato N, Tateishi R, Muroyama R, Kowatari N, Li W, Goto K, Otsuka M, Shiina S, Yoshida H, Omata M, Koike K.
    • Journal Title

      Hepatology Research

      Volume: :

    • DOI

      10.1111/hepr.12258

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk.2014

    • Author(s)
      Lo PH, Urabe Y, Kumar V, Tanikawa C, Koike K, Kato N, Miki D, Chayama K, Kubo M, Nakamura Y, Matsuda K.
    • Journal Title

      Plos one

      Volume: 8

    • DOI

      10.1371/journal.pone.0061279

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A genome-wide association study of HCV-induced liver cirrhosis in the Japanese populationidentifies novel susceptibility loci at the MHC region2013

    • Author(s)
      Otsuka M
    • Journal Title

      Journal of Hepatology

      Volume: I(n press) Pages: 875-882

    • DOI

      10.1016/j.jhep.2012.12.024

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The AMPK-Related Kinase SNARK Regulates Hepatitis C Virus Replication and Pathogenesis Through Enhancement of TGF-β Signaling2013

    • Author(s)
      Goto K, Lin W, Zhang L, Jilg N, Shao RX, Schaefer EA, Zhao H, Fusco DN, Peng LF, Kato N, Chung R T.
    • Journal Title

      Journal of Hepatology

      Volume: 59 Pages: 942-948

    • DOI

      10.1016/j.jhep.2013.06.025

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] GWAS肝癌感受性遺伝子MICAを介した腫瘍免疫監視.2015

    • Author(s)
      後藤 覚、加藤直也.
    • Organizer
      第3回肝炎ウイルス研修会
    • Place of Presentation
      東京
    • Year and Date
      2015-02-26 – 2015-02-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] NK cell anti-tumor activity was boosted by SAHA identified to induce the expression of a GWAS-discovered HCV-HCC susceptibility gene MICA.2014

    • Author(s)
      Goto K, Muroyama R, Li W, Nakagawa R, Matsubara Y, Kato N.
    • Organizer
      The Liver Meeting 2014
    • Place of Presentation
      Boston, USA
    • Year and Date
      2014-11-07 – 2014-11-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] B型肝癌感受性遺伝子MICAの発現制御による肝発癌抑止戦略.2014

    • Author(s)
      加藤直也、後藤 覚、室山良介.
    • 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
    • Related Report
      2014 Annual Research Report
  • [Presentation] Potentiated anti-tumor activity of NK cells by an approved drug identified to induce the expression of a GWAS-discovered HCV-HCC susceptibility gene MICA.2014

    • Author(s)
      Goto K, Muroyama R, Li W, Nakagawa R, Matsubara Y, Kato N.
    • Organizer
      21st International Symposium on Hepatitis C Virus and Related Viruses
    • Place of Presentation
      Banff, Canada.
    • Year and Date
      2014-09-07 – 2014-09-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] HBV induces an HBV-insuced HCC associated gene MICA through transcriptional activation in SNPS dependent manner.2014

    • Author(s)
      Muroyama R, Goto K, Li W, Matsubara Y, Nakagawa R, Ito S, Kato N.
    • Organizer
      2014 International Meeting on Molecular Biology of Hepatitis B Viruses
    • Place of Presentation
      Los Angeles, USA
    • Year and Date
      2014-09-03 – 2014-09-06
    • Related Report
      2014 Annual Research Report
  • [Presentation] GWASにより見出された肝癌関連遺伝子MICAの発現増強による新たな肝発癌抑止法の開発.2014

    • Author(s)
      加藤直也、後藤 覚、室山良介、中川 良、李 ウェンウェン、伊藤彩弥香、松原康朗.
    • Organizer
      第10回広島肝臓プロジェクト研究センターシンポジウム
    • Place of Presentation
      広島
    • Year and Date
      2014-07-05
    • Related Report
      2014 Annual Research Report
  • [Presentation] GWASにより同定された肝癌感受性遺伝子MICAの発現制御を介した肝発癌抑止戦略.2014

    • Author(s)
      後藤 覚、 室山良介、 加藤直也.
    • Organizer
      第50回日本肝臓学会総会
    • Place of Presentation
      東京
    • Year and Date
      2014-05-29 – 2014-05-30
    • Related Report
      2014 Annual Research Report
  • [Presentation] 腫瘍自然免疫を司るMICAのB型およびC型肝癌における役割.2014

    • Author(s)
      室山良介、 後藤 覚、 松田浩一、 田中靖人、 茶山一彰、 溝上雅史、 小俣政男、 小池和彦、 加藤直也.
    • Organizer
      第50回日本肝臓学会総会
    • Place of Presentation
      東京
    • Year and Date
      2014-05-29 – 2014-05-30
    • Related Report
      2014 Annual Research Report
  • [Presentation] IL28B SNPがC型慢性肝炎患者における肝線維化・炎症・脂肪化に与える影響-メタアナリシスによる検討.2014

    • Author(s)
      佐藤雅哉、 近藤真由子、 建石良介、 加藤直也、 吉田晴彦、 小池和彦.
    • Organizer
      第50回日本肝臓学会総会
    • Place of Presentation
      東京
    • Year and Date
      2014-05-29 – 2014-05-30
    • Related Report
      2014 Annual Research Report
  • [Presentation] C型肝癌に対するラジオ波焼灼術後の再発, 予後に対するMICA, DEPDC5, IL28B, PNPLA3遺伝子多型の意義の検討.2014

    • Author(s)
      佐藤雅哉、 加藤直也、 小池和彦.
    • Organizer
      第50回日本肝臓学会総会
    • Place of Presentation
      東京
    • Year and Date
      2014-05-29 – 2014-05-30
    • Related Report
      2014 Annual Research Report
  • [Presentation] Impact of IL28B genetic variation on HCV-induced liver fibrosis, inflammation, and steatosis: a meta-analysis.2014

    • Author(s)
      Sato M, Kondo M, Tateishi R, Kato N, Yoshida H, Koike K.
    • Organizer
      49th annual meeting of the European Association for the Study of the Liver
    • Place of Presentation
      London, United Kingdom
    • Year and Date
      2014-04-09 – 2014-04-13
    • Related Report
      2014 Annual Research Report
  • [Presentation] MICA plays an opposite role in hepatocarcinogenesis between hepatitis B and hepatitis C.2013

    • Author(s)
      Naoya Kato, Vinod Kumar, Ryosuke Muroyama, Ryosuke Tateishi, Yasuhito Tanaka, Masashi Mizokami, Masao Omata, Kazuhiko Koike, Koichi Matsuda.
    • Organizer
      48th Annual Meeting of the European Association for the Study of the Liver
    • Place of Presentation
      Amsterdam, Netherlands
    • Related Report
      2013 Annual Research Report
  • [Presentation] Effective inducers of a GWAS-discovered anti-HCC gene MICA.2013

    • Author(s)
      Kaku Goto, Ryosuke Muroyama, Wenwen Li, Norie Kowatari, Ryo Nakagawa, Naoya Kato.
    • Organizer
      20th International Symposium on Hepatitis C Virus and Related Viruses
    • Place of Presentation
      Melbourne, Australia
    • Related Report
      2013 Annual Research Report
  • [Presentation] MICA might have opposite effect on hepatocarcinogenesis between B-HCC and C-HCC.2013

    • Author(s)
      Ryosuke Muroyama, Vinod Kumar, Kaku Goto, Norie Kowatari, Wenwen Li, Ryo Nakagawa, Ryosuke Tateishi, Yasuhito Tanaka, Masashi Mizokami, Masao Omata, Kazuhiko Koike, Koichi Matsuda, Naoya Kato.
    • Organizer
      2013 International Meeting on Molecular Biology of Hepatitis B Viruses
    • Place of Presentation
      Shanghai, China
    • Related Report
      2013 Annual Research Report
  • [Presentation] An HCV-HCC susceptibility gene MICA found in GWAS was effectively induced by HDAC inhibitors.2013

    • Author(s)
      Kaku Goto, Ryosuke Muroyama, Wenwen Li, Norie Kowatari, Ryo Nakagawa, Naoya Kato.
    • Organizer
      The 64th Annual Meeting of the American Association for the Study of Liver Diseases
    • Place of Presentation
      Washington, DC, U.S.A.
    • Related Report
      2013 Annual Research Report
  • [Presentation] 肝発癌において自然免疫関連分子MICAはB型肝炎とC型肝炎では反対の役目を担っている.2013

    • Author(s)
      加藤直也、室山良介、小池和彦.
    • Organizer
      第49回日本肝臓学会総会
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] GWAS により同定された肝癌感受性遺伝子MICA の発現を誘導する薬剤の探索.2013

    • Author(s)
      後藤 覚、室山良介、李 雯雯、中川 良、古渡礼恵、加藤 直也.
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
  • [Presentation] ゲノムワイド関連解析によるC型肝硬変/肝癌の感受性遺伝子の同定.2013

    • Author(s)
      室山良介、松田浩一、加藤直也.
    • Organizer
      第17回日本肝臓学会大会
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] HDAC inhibitors are potent suppressors of HCV-induced hepatocarcinogenesis by upregulating MICA a GWAS-identified HCC susceptibility gene.2012

    • Author(s)
      Goto K, Kato N, et al.
    • Organizer
      The 63th Annual Meeting of the American Assoclation for the Study of Liver Diseases
    • Place of Presentation
      Boston, USA
    • Year and Date
      2012-11-13
    • Related Report
      2012 Annual Research Report
  • [Presentation] C型肝癌感受性を決定する遺伝子MICAを誘導する薬剤による肝発癌抑止法の開発2012

    • Author(s)
      後藤 覚、加藤直也, ほか
    • Organizer
      第16回肝臓学会大会
    • Place of Presentation
      神戸国際展示場(神戸市)
    • Year and Date
      2012-10-10
    • Related Report
      2012 Annual Research Report
  • [Presentation] Exploration for inducers of MICA, a GWAS-identif ied genetic susceptibility factor for HCV-induced HCC.2012

    • Author(s)
      Goto K, Kato N, et al.
    • Organizer
      19th Internatlonal Symposium on Hepatitis C Virus and Related Viruses
    • Place of Presentation
      Venice, Italy
    • Year and Date
      2012-10-06
    • Related Report
      2012 Annual Research Report
  • [Presentation] C型肝癌感受性遺伝子MICAを誘導する薬剤の探索2012

    • Author(s)
      後藤 覚、加藤直也, ほか
    • Organizer
      第48回日本肝臓学会総会
    • Place of Presentation
      ポルテ金沢(金沢市)
    • Year and Date
      2012-06-08
    • Related Report
      2012 Annual Research Report

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Published: 2012-04-23   Modified: 2019-07-29  

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