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

• Project/Area Number: 24390184
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The 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: ¥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.

Research Products

• [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 Issue: 3 Pages: 261-272
  • DOI: 10.1007/s00535-014-1000-9
  • 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
  • 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 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: J Gastroenterol Volume: 49(4) Issue: 4 Pages: 748-54
  • DOI: 10.1007/s00535-013-0826-x
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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
  • 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 Issue: 3 Pages: e91822-e91822
  • DOI: 10.1371/journal.pone.0091822
  • Peer Reviewed / Open Access
• [Journal Article] Impact of PNPLA3 polymorphisms on the development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. (2013)
  • 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: Hepatol Res. Volume: : Issue: 10
  • DOI: 10.1111/hepr.12258
  • Peer Reviewed
• [Journal Article] Identification of a Functional Variant in the MICA Promoter Which Regulates MICA Expression and Increases HCV-Related Hepatocellular Carcinoma Risk. (2013)
  • 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 Issue: 4 Pages: e61279-e61279
  • DOI: 10.1371/journal.pone.0061279
  • Peer Reviewed
• [Journal Article] A genome-wide association study of HCV-induced liver cirrhosis in the Japanese populationidentifies novel susceptibility loci at the MHC region (2013)
  • Author(s): Otsuka M
  • Journal Title: J Hepatol Volume: I(n press) Issue: 5 Pages: 875-882
  • DOI: 10.1016/j.jhep.2012.12.024
  • Peer Reviewed
• [Journal Article] The AMPK-Related Kinase SNARK Regulates Hepatitis C Virus Replication and Pathogenesis Through Enhancement of TGF-β Signaling (2013)
  • 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 Issue: 5 Pages: 942-948
  • DOI: 10.1016/j.jhep.2013.06.025
  • 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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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.
• [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
• [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
• [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
• [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
• [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
• [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
• [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