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Analysis of the molecular mechanism of hepatocarcinogenesis in patients with chronic viral diseases and its application for genetic diagnosis of hepatocellular carcinoma.

Research Project

Project/Area Number 10470135
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionOsaka University

Principal Investigator

KASAHARA Akinori  School of Medicine, Osaka Univ, Associate Professor, 医学部・附属病院, 助教授 (70214286)

Co-Investigator(Kenkyū-buntansha) MOCHIZUKI Kiyoshi  School of Medicine, Osaka Univ, 医学部・附属病院, 医員
HIRAMATSU Naoki  School of Medicine, Osaka Univ, 医学部・附属病院, 医員
SASAKI Yutaka  Graduate School of Medicine, Osaka Univ, Associate Professor, 医学系研究科, 助教授 (70235282)
OHKAWA Kazuyoshi  School of Medicine, Osaka Univ, 医学部・附属病院, 医員
考藤 達哉  大阪大学, 医学部・附属病院, 医員
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥4,700,000 (Direct Cost: ¥4,700,000)
KeywordsHepatitis C virus / hepatocellular carcinoma / extended haplotype / TAP / dendric cell / B7-1 / IL-12 / interferon / B型肝炎 / 遺伝子診断 / B7-1 / Fas
Research Abstract

Extended haplotypes including class I B54 is demonstrated to be associated with the progression of liver injury, whereas extended haplotypes including class II DRB1^*1302-DQB1^*0604 and TAP2^*0103 to be associated with low hepatitis activity in chronic HCV infection. Thus, single nucleotide polymorphism may be related to the development and/or progression of liver disease in patients with chronic HCV infection.
MAPK/ERK activation in human hepatcellular carcinoma (HCC) is shown to play an important role in multistep hepatocarcinogenesis, especially in the progression of HCC through cyclin D1 up-regulation primarily induced by MAPK/ERK via c-fos.
The stimulatory potentials of dendric cells from patients with HCV infection are impaired against alloantigens but not against recall antigens. The possible mechanism for such impairment are their low expression of CD86 and/or IL-12 at the baseline, and low allogenic response could be overcome by the addition of IL-2 or IL-12. However, when dendr … More ic cells from patients with HCV-infection encounter recall antigens, they are activated to restore the potentials for cytokine production and stimulation of T cell proliferation. The combination of immunization of B7-1-transfected HCC cells and IL-12 could induce protective and therapeutic immunity against parental HCC cells, and this combination therapy may be useful for suppressing recurrence of HCC.
Interferon therapy lowered the incidence of HCC among ratients with chronic hepatitis C showing transient normalization of ALT as well as sustained normalization of ALT after the completion of interferon therapy. Moreover, survival analyses and determination of cause of death suggest that interferon therapy improves the long-term survival of chronic hepatitis C patients who responded to this therapy, possibly by decreasing mortality from liver-related diseases.
These findings may lead to clarify the mechanism of the development of liver damage and hepatocellular carcinoma and to improve the long-term clinical outcome of patients with chronic HCV infection. Less

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (42 results)

All Other

All Publications (42 results)

  • [Publications] Kuzushita N, et al.: "Influence of HLA haplotype on the clinical courses of individuals infected with hepatitis C virus."Hepatology. 27. 240-247 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito Y, et al.: "Activation of mitogen-activated protein kinases / extraoellular signalrelated kinases in human hepatocellular carcinoma."Hepatology. 27. 951-958 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kasahara A, et al.: "Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C."Hepatology. 27. 1394-1402 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takehara T, et al.: "Delayed Fas-mediated hepatocyte apoptosis during liver regeneration in mice : Hepatoprotective role of TNF-α."Hepatology. 27. 1643-1651 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wada S, et al.: "Involvement of growth factor receptor-bound protein-2 in rat hepatocyte growth."J Gastroenterol Hepatol. 13. 635-642 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iio S, et al.: "Serum levels of soluble Fas antigen in chronic hepatitis C patients."J Hepatol. 29. 517-523 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka Y, et al.: "Probability of hepatocellular carcinoma of small hepatocellular nodules undetectable by coputed tomography during arterial portography."Hepatology. 31. 890-898 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kasahara A, et al.: "Clinical characteristics of chronic hepatitis C patients showing biochemical remission without hepatitis C virus eradication by interferon treatment."J Viral.Hepatitis. 7. 343-351 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka H, et al.: "Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C : a retrospective cohort study of 738 patients."Int J Cancer. 87. 741-749 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kanto T, et al.: "Impaired allostimulatory capacity of peripheral blood dendric cells recovered from hepatitis C-virus-infected individuals."J Immunol. 162. 5584-5591 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kuzushita N, et al.: "Involvement of transporter-associated with antigen processing 2 (TAP2) gene polymorphisms in hepatitis C virus infection."Gastroenterology. 116. 1149-1154 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamamoto M, et al.: "Intracellular single-chain antibody against hepatitis B virus core protein inhibits the replication of hepatitis B virus in cultured cells."Hepatology. 30. 300-307 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tatsumi T, et al.: "B7-1(CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma."Hepatology. 30. 422-429 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takehara T, et al.: "Interleukin 1β protects mice form Fas-mediated hepatocyte apoptosis and death."Gastroenterology. 117. 661-668 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishida H, et al.: "Identification of multiple transcription factors, HLF, FIF, and E4BP4, controlling hepatitis B virus enhancer II."J Virol. 74. 1241-1451 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kuzushita N, et al.: "Influence of HLA haplotype on the clinical courese of individuals infected with hepatitis C virus."Hepatolgy. 27. 240-247 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito Y, et al.: "Activation of mitogen-activated protein kinases/extracellular signal-related kinases in human hepatocellular carcinoma."Hepatology. 27. 951-958 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kasahara A, et al.: "Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C"Hepatology. 27. 1394-1402 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takehara T, et al.: "Delayed Fas-mediated hepatocyte apoptosis during liver regeneration in mice : hepatoprotective role of TNF-."Hepatology. 27. 1643-1651 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kanto T, et al.: "Impaired allostimulatory capacity of peripheral blood dendric cells recovered from hepatitis C-virus-infected individuals."J Immunol. 162. 5584-5591 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamanto N, et al.: "Intracellular single-chain antibody against hepatitis B virus core protein inhibits the replication of hepatitis B virus in cultured cells."Hepatology. 30. 300-307 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tatsumi T, et al.: "B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouce hepatocellular carcinoma."Hepatology. 30. 422-429 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takehara T, et al.: "Interleukin 1 protects mice from Fasmediated hepatocyte apoptosis and death."Gastroenterology. 117. 661-668 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kuzushita N, et al.: "Involvement of transporter-associated with antigen procoessing 2 (TAP2) gene polymorphism in hepatitis C virus infection."Gastroenterology. 116. 1149-1154 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishida H, et al.: "Identification of multiple transcription factors, HLF, FIF, and E4BP4, controlling hepatitis B virus enhancer II."J Virol. 74. 1241-1251 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kasahara A, et al.: "Clinical characterristics of chronic hepatitis C patients showing biochemical remission without hepatitis C virus eradication by interferon treatment."J Viral Hepatitis. 7. 343-351 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka H, et al.: "Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patient with chronic hepatitis C : a retrospective cohort study of738 patients."Int J Cancer. 87. 741-749 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishida H, et al.: "Identification of multiple transcription factors, HLF, FTF,and E4BP4, controlling hepatitis B enhancer."J Virol. 74. 1241-1251 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kasahara A, et al.: "Pretreatment viral load and response to interferon therapy for liver cirrhosis caused by hepatitis C virus."Hepatol Res. 16. 124-138 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanaka Y, et al.: "Probability of hepatocellular carcinoma of small hepatocellular nodules undetectable by computed tomography during arterial portography."Hepatology. 31. 890-898 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kasahara A, et al.: "Clinical characteristics of chronic hepatitis C patients showing biochemical remission without hepatitis C virus eradication by interferon treatment."J Viral Hepatitis. 7. 343-351 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanaka H, et al.: "Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C.a retrospective cohort of 738 pattents."Int J Cancer. 87. 741-749 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kanto T, et al.: "Impaired allostimulatory capacity of peripheral blood dendric cells recovered from hepatitis C virus infected individuals"J Immunol. 162. 5584-5591 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kuzushita N, et al.: "Involvement of transporter associated with antigen processing(TAP2) gene polymorphisms in hepatitis C virus infection"Gastroenterology. 116. 1149-1154 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tatsumi T, et al.: "B7-1(CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma"Hepatology. 30. 422-429 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamamoto M, et al.: "Intracellular single-chain antibody against hepatitis B virus core protein inhibits the replication of hepatitis B virus in cultured cells"Hepatology. 30. 300-307 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kuzushita N,et al: "Influence of HLA haplotypes on the clinical courses of individuals infected with hepatitis C virus." Hepatology. 27. 240-244 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ito Y,et al: "Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma." Hepatology. 27. 951-958 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kasahara A,et al.: "Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C." Hepatology. 27. 1394-1402 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takehara T,et al.: "Delayed Fas-mediated hepatocyte apotosis during liver regeneration in mice : Hepatoprotective role of TNFd" Hepatology. 27. 1643-1651 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kanto N,et al.: "Cross-linking of Fcγ-receptor on monocytes inhibits hepatitis C virus-specific cytotoxic T-lymphocyte induction in vitro." Immunology. 94. 461-468 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Iio S,et al.: "Serum levels of soluble Fas antigen in chronic hepatitis C patients." J Hepatol. 29. 517-523 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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