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2007 Fiscal Year Final Research Report Summary

Pathogenesis of chronic hepatitis C and hepatocellular carcinoma and predictive factors determined by data mining

Research Project

Project/Area Number 18590724
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionUniversity of Yamanashi

Principal Investigator

ASAHINA Yasuhiro  University of Yamanashi, Deparment of Research Interdisciplinary, Graduate School of Medicine and Engineering, Research Fellow (00422692)

Co-Investigator(Kenkyū-buntansha) IZUMI Mamiki  University of Yamanashi, Deparment of Research Interdisciplinary, Graduate School of Medicine and Engineering, Research Fellow (20397300)
ENOMOTO Nobuyuki  University of Yamanashi, Deparment of Research Interdisciplinary, Graduate School of Medicine and Engineering, professor (20251530)
KUROSAKI Masayuki  University of Yamanashi, Deparment of Research Interdisciplinary, Graduate School of Medicine and Engineering, Research Fellow (10280976)
Project Period (FY) 2006 – 2007
KeywordsChronic henatic C / interferon / ribavirin / innate immunity
Research Abstract

BACKGROUND: Mechanisms involving resistance to interferon (IFN) and ribavirin (RBV) have wit been fully elucidated, and prediction of treatment responses before initiation of therapy is difficult. RIG-I and the related MDA5 initiate the host antiviral response by detecting intracellular viral dsRNA. Cardif (ISP-I, MAVS, VISA) is an adaptor molecule that connects RIG-I sensing to downstream signaling. On the other hand, LGP2, a helicase belonging RIG-I family, and an E3 ubiquitin ligase have been shown to negatively regulate RIG-I sensing. Moreover, these molecules are ISGylated by ISG15, a ubiquitin-like protein However; the clinical significance of these innate immune systems in terms of treatment response is unclear.
AIM: To elucidate the mechanisms underlying resistance to PEG-IFN plus RBV, and to determine whether analysis of the innate immune system is useful in predicting treatment responses.
METHODS: We studied 74 chronic hepatitis C virus (HCV) patients with genotype lb treated w … More ith PEG-IFN alfa-2b plus RBV for 48 weeks and 5 patients with non-viral liver disease. Pretreatment hepatic mRNA expressions of RIG-I, Cardif MDA5, LGP2, ISG15, USP18 (a specific remover of ISMS from ISGylated protein), and serum HCV dynamics during therapy were measured by real-time PCR. G3PDH and HMB were used as internal controls.
RESULTS: Thirty-four patients were sustained virological responders (SVR), 24 were transient responders (TR), and 20 were non-virological responders (NVR). The hepatic levels of all transcripts except Cardif were 2. to 8-fold higher in HCV patients than non-HCV patients. RIG-I, MDA5, and LGP2 expression was significantly up-regulated in NVR compared with TR or SVR. Cardif expression negatively correlated with RIG-I expression and was significantly suppressed in NVR. The difference between NVR and SVR or TR in the RIG-I/Cardif expression ratio was pronounced (NVR/PR/SVR = 1.2/0.6/0.5 copies/control). Like RIG-I and MDA5, ISG15 and USP18 expression was significantly up-regulated in NVR (ISG15, NVR/TR/SVR = 0.8/0.4/0.2 copies/control; USP18, NVRTR/SVR = 0.9/0.6/0.4 copies/control). The RIG-I/Cardif ratio and the expression of MDA5, ISG15, and USP18 significantly correlated with viral decline rates in the first and second phases of HCV dynamics. Multivariate and ROC analyses revealed that a higher ratio of RIG-I/Cardif and a higher expression of MDA5, ISG15, and USP18 predicted NW.
CONCLUSION: Intracellular sensors and their regulators were variously up-regulated upon HCV infection especially in NVR Quantifying hepatic gene expression involving an innate immune system is of use in identifying patients who are at a higher risk for NVR. Less

  • Research Products

    (16 results)

All 2008 2007 2006 Other

All Journal Article (10 results) (of which Peer Reviewed: 5 results) Presentation (6 results)

  • [Journal Article] Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response2008

    • Author(s)
      朝比奈 靖浩, 他
    • Journal Title

      Gastroenterology (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] The presence of steatosis and elevation of ALT levels are associated with fibrosis progression in chronic hepatitis C with non-response to IFN2008

    • Author(s)
      黒崎 雅之, 他
    • Journal Title

      Journal of Hepatology 48

      Pages: 736-742

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] The presence of steatosis and elevation of ALT levels are associated with fibrosis progression in chronic hepatitis C with non-response to IFN2008

    • Author(s)
      Masayuki, Kurosaki, et. al.
    • Journal Title

      Journal of Hepatology 48

      Pages: 736-742

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Pharmacokinetics and enhanced PKR response in patients with chronic hepatitis C treated with pegylated interferon alpha-2b and ribavirin.2007

    • Author(s)
      朝比奈 靖浩, 他
    • Journal Title

      J Viral Hepat 14

      Pages: 396-403

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Influence of hepatitis B virus X and core promoter mutations on hepatocellular carcinoma among patients infected with subgenotype C2.2007

    • Author(s)
      朝比奈 靖浩, 他
    • Journal Title

      J Clin Microbiol 45

      Pages: 3191-7

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Repeated radiofrequency ablation for the distant recurrence in the liver in patients with chronic hepatitis C virus infection achieving long-term survival.2007

    • Author(s)
      泉 並木, 他
    • Journal Title

      Hepatol Res Suppl 2

      Pages: S254-63

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Pharmacokinetics and enhanced PKR response in patients with chronic hepatitis C treated with pegylated interferon alpha-2b and ribavirin2007

    • Author(s)
      Yasuhiro, Asahina, et. al.
    • Journal Title

      J Viral Hepat 14

      Pages: 396-403

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Influence of hepatitis B virus X and core promoter mutations on hepatocellular carcinoma among patients infected with subgenotype C22007

    • Author(s)
      Yasuhiro, Asahina, et. al.
    • Journal Title

      J Clin Microbiol 45

      Pages: 3191-7

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Repeated radiofrequency ablation for the distant recurrence in the liver in patients with chronic hepatitis C virus infection achieving long-term survival2007

    • Author(s)
      Namiki, Izumi, et. al.
    • Journal Title

      Hepatol Res Supple 2

      Pages: 254-63

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response

    • Author(s)
      Yasuhiro, Asahina, et. al.
    • Journal Title

      Gastroenterology inpress

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Gene expression involving innate interferon-regulatory immunity and resistance to peg-interferon alfa-2b plus ribavirin treatment in chronic hepatitis C2007

    • Author(s)
      朝比奈靖浩, 他
    • Organizer
      米国肝臓学会(AASLD)
    • Place of Presentation
      ボストン市
    • Year and Date
      20071000
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Gene expression involving innate interferon-regulatory immunity and resistance to peg-interferon alfa-2b plus ribavirin treatment in chronic hepatitis C2007

    • Author(s)
      Yasuhiro, Asahina, et. al.
    • Organizer
      AASLD
    • Place of Presentation
      Boston
    • Year and Date
      20071000
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Gene expression involving interferon-regulatory innate immunity and resistance to PEG-IFN/RBV treatment in chronic hepatitis C2006

    • Author(s)
      朝比奈靖浩, 他
    • Organizer
      米国肝臓学会
    • Place of Presentation
      ボストン市
    • Year and Date
      20061000
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Probability and risk factors for exceeding the Milan criteria after successful RFA in patients with HCC2006

    • Author(s)
      朝比奈靖浩, 他
    • Organizer
      米国肝臓学会
    • Place of Presentation
      ボストン市
    • Year and Date
      20061000
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Gene expression involving interferon-regulatory innate immunity and resistance to PEG-IFN/RBV treatment in chronic hepatitis C2006

    • Author(s)
      Yasuhiro, Asahina, et. al.
    • Organizer
      AASLD
    • Place of Presentation
      Boston
    • Year and Date
      20061000
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Probability and risk factors for exceeding the Milan criteria after successful RFA in patients with HCC2006

    • Author(s)
      Yasuhiro, Asahina, et. al.
    • Organizer
      AASLD
    • Place of Presentation
      Boston
    • Year and Date
      20061000
    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2010-02-04  

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