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The role of hepatitis C infection and proliferators-activated receptor alpha protects (PPA α) in occurrence of hepatocellular carcinoma

Research Project

Project/Area Number 15590633
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionShinshu University School of Medicine

Principal Investigator

KIYOSAWA Kendo  Shinshu University School of Medicine, Department of Internal Medicine (Gastroenterology), Professor, 医学部, 教授 (30020829)

Co-Investigator(Kenkyū-buntansha) AOYAMA Toshihumi  Shinshu University Graduate School of Medicine, Department of Metabolic Regulation, Institute on Aging and Adaptation, Professor, 医学研究科, 教授 (50231105)
TANAKA Eiji  Shinshu University School of Medicine, Department of Internal Medicine (Gastroenterology), Associate Professor, 医学部, 助教授 (50163506)
YOSHIZAWA Kaname  Shinshu University School of Medicine, Department of Internal Medicine (Gastroenterology), Assistant Professor, 医学部, 講師 (90220615)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordshepatitis C virus (HCV) / HCV core protein / PPARα / steatosis / hepatocellular carcinoma (HCC) / PPAR-α
Research Abstract

Persistent infection of hepatitis C virus (HCV) can lead to a high risk for hepatocellular carcinoma (HCC). Hepatitis C virus core protein (HVB core protein) plays important roles in HCV-related hepatocarcinogenesis, because its expression in mice causes hepatic steatosis and HCC without accompanuing hepatitis. To clarify whether the HCV core protein alters the expression of the factors associated with hepatic steatosis and HCC in vivo, expression of the proteins including oncogene products, sell cycle regulators and fatty acid-metabolizing enzymes, was investigated. The expression of numerous proteins, which is induced by the activation of peroxisome proliferators-activated receptor α (PPAR α), increased simultaneously and age-dependently in HCV core protein transgenic mouse. In these mice, stabilization and activation of nuclear PPAR α occurred, probably due to increased nuclear free fatty acids, endogenous PPAR actovators, and due to the interaction with HCV core protein. Persistent and heterogenous activation of PPAR a seemed to disturb the homeostasis in hepatocytes proliferation/removal, resulting in casing age-dependent appearance of aberrant hepatocytes, overexpression PPAR α or cycline D1, in scattered areas of the liver. These aberrant hepatocytes proliferated and tend to form multicentric clusters. These phenomena were entirely different from those observed in the rodents treated with nongenotoxic carcinogens such as fibrates. These results offer the first suggestion that persistent and heterogenous activation of PPAR α can contribute to age-dependent and multicentric hepatocarcinogenesis caused by HCV infection.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (24 results)

All 2004 2003 Other

All Journal Article (18 results) Publications (6 results)

  • [Journal Article] Hepatocellular carcinoma : recent trends in Japan2004

    • Author(s)
      Kiyosawa K et al.
    • Journal Title

      Gastroenterology 127

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Peroxisome proliferators-activated receptor alpha protects against alcohol-induced liver damage2004

    • Author(s)
      Nakajima T, Kiyosawa K et al.
    • Journal Title

      Hepatology 40

      Pages: 972-980

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Types of human leucocytes antigen and decrease in HCV core antigen in serum for predicting efficacy of interferon-alpha in patients with chronic hepatitis2004

    • Author(s)
      Muto H, Kiyosawa K et al.
    • Journal Title

      J Gastrenterol 39

      Pages: 674-680

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phlebotomy : a promising treatment for chronic hepatitis C2004

    • Author(s)
      Tanaka N, Kiyosawa K
    • Journal Title

      J Gastrenterol 39

      Pages: 601-603

    • NAID

      10013296521

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] C型肝炎ウイルスによる肝細胞癌発症のメカニズム-PPARαの役割2004

    • Author(s)
      田中 直樹, 青山 俊文
    • Journal Title

      Cancer 101

      Pages: 1616-1622

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatocellular carcinoma : recent trends in Japan2004

    • Author(s)
      Kiyosawa K, Umemura T, Ichijo T, Matsumoto A, Yosgizawa K, Gad A, Tanaka E.
    • Journal Title

      Gastroenterology 127

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] peroxisome proliferators-activated receptor alpha Protects against alcohol-induced liver damage.2004

    • Author(s)
      Nakajima T, Kamijo Y, Tanaka N, Sugiyama E, Tanaka E, Kiyosawa K, Fukushima Y, Peters JM, Gonzalez FJ, Aoyama T.
    • Journal Title

      Hepatology 40

      Pages: 972-980

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Types of human leucocyte antigen and decrease in HCV core antigen in serum for predicting efficacy of interferon-α in patients with chronic hepatitis C : analysis by a prospective study.2004

    • Author(s)
      Muto H, Tanaka E, Matsumoto A, Yoshizawa K, Kiyosawa K.
    • Journal Title

      J Gastroenterol 39

      Pages: 674-680

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Interferon therapy for aged patients with chronic hepatitis C : improved survival in patients exhibiting a biochemical response.2004

    • Author(s)
      Imai Y, Kasahara A, Tanaka H, Okanoue T, Hiramatsu N, Tsubouchi H, Yoshioka K, Kawata S, Tanaka E, Hino K, Hayashi K, Tamura S, Itoh Y, Sasaki Y, Kiyosawa K, Kakumu S, Okita K, Hayashi N.
    • Journal Title

      J Gastroenterol 39

      Pages: 1069-1077

    • NAID

      10014116243

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Characteritics of patients with chronic hepatitis C who develop hepatocellular carcinoma after a sustained response to interferon therapy.2004

    • Author(s)
      Makiyama A, Itoh Y, Kasahara A, Imai Y, Kawata S, Yoshioka K, Tsubouchi H, Kiyosawa K, Kakumu S, Okita K, Hayashi N, Okanoue T.
    • Journal Title

      Cancer 101

      Pages: 1616-1622

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Peroxisome proliferators-activated receptor alpha protects against alcohol-induced-liver damage2004

    • Author(s)
      Nakajima T, Kiyosawa K et al.
    • Journal Title

      Hepatology 40

      Pages: 972-980

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Phlebotomy : a promising treatment for chronic hepatitis C2004

    • Author(s)
      Tanaka N, Kiyosawa K
    • Journal Title

      J Gastroenterol 39

      Pages: 601-603

    • NAID

      10013296521

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Types of human leucocytes antigen and decrease in HCV core antigen in serum for predicting efficacy of interferon-alpha in patients with chronic hepatitis C2004

    • Author(s)
      Muto H, Kiyosawa K et al.
    • Journal Title

      J Gastroenterol 39

      Pages: 674-680

    • Related Report
      2004 Annual Research Report
  • [Journal Article] C聖肝炎ウイルスによる肝癌発症のメカニズム-PPARαの役割2004

    • Author(s)
      田中 直樹, 青山 俊文
    • Journal Title

      日本臨牀 62

      Pages: 20-25

    • Related Report
      2004 Annual Research Report
  • [Journal Article] PPARαと脂肪代謝異常2004

    • Author(s)
      田中 直樹, 青山 俊文
    • Journal Title

      Medical Science Disease 30

      Pages: 62-65

    • Related Report
      2004 Annual Research Report
  • [Journal Article] In vitro stabilization of nuclear retinoide X receptor alpha in the presence of peroxisome proliferators-activated receptor alpha.2003

    • Author(s)
      Tanaka N, Hora K, Makishima H, Kamijo Y, Kiyosawa K, Gonzalez FJ, Aoyama T.
    • Journal Title

      FEBS Lett 543

      Pages: 120-124

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Long-term follow-up of hepatitis C virus Infection : HLA class II loci influences the natural history of the disease.2003

    • Author(s)
      Yoshizawa K, Ota M, Saito S, Maruyama A, Yamaura T, Rokuhara A, Orii K, Ichijo T, Matsumoto A, Tanaka E, Kiyosawa K.
    • Journal Title

      Tissue Antigens 61

      Pages: 159-165

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Factors predisposing to the ocuurence of cryoglobulinemia in two cohorts of Egyptian and Japanese patients with chronic hepatitis C infection : ethinic and genotypic influence.2003

    • Journal Title

      J Med Virol 70

      Pages: 594-599

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Tanaka N, Hora K, Kiyosawa K, Aoyama T et al.: "In vivo stabilization of nuclear retinoid X receptor α in the presence of peroxisome proliferator-activated receptor-α"FEBS Letters. 543. 120-124 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Aoki Y, Cioca H, Oidaira H, Kamiya J, Kiyosawa K: "RNA interference may be more potent than antisense RNA in human cancer cell lines"Clin Experim Pharmaco Physiol. 30. 96-102 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanaka N, Kiyosawa K: "Development of hepatocellular carcinoma after longterm sustained complete response to interferon therapy"J Gastroenterol. 38. 417-419 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshizawa, K, Tanaka E, Kiyosawa K et al.: "Long-term follow-up of hepatitis C virus infection : HLA class II loci influences the natural history of the disease"Tissue Antigens. 61. 159-165 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Amal Gad, Tanaka E, Yoshizawa K, Kiyosawa K et al.: "Factors predisposing to the occurrence of cryoglobulinemia in two cohorts of Egyptian and Japanese patients with chronic hepatitis C infection : Ethnic and genotypic influence"J Med Virol. 70. 594-599 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 田中直樹, 清澤研道: "NASHの成因と病態:(3)肝炎ウイルスとNASH"臨床消化器内科. 18(9). 1269-1274 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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