2000 Fiscal Year Final Research Report Summary
Analysis of the molecular mechanism of hepatocarcinogenesis in patients with chronic viral diseases and its application for genetic diagnosis of hepatocellular carcinoma.
| Project/Area Number |
10470135
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
KASAHARA Akinori School of Medicine, Osaka Univ, Associate Professor, 医学部・附属病院, 助教授 (70214286)
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| 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
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| Project Period (FY) |
1998 – 2000
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| Keywords | Hepatitis C virus / hepatocellular carcinoma / extended haplotype / TAP / dendric cell / B7-1 / IL-12 / interferon |
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| 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
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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
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