Modification of Cell Growth Regulation by Hepatitis C virus

丙型肝炎病毒对细胞生长调节的修饰

• 批准号: 10670295
• 负责人: KOHARA Kyoko
• 金额: $ 2.05万
• 依托单位: TOKYO METROPOLITAN ORGANIZATION FOR MEDICAL RESEARCH, THE TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670295/
• 关键词: HCV; Cre; loxP expression system; HCV expressing cell line; HCV Tg mouse; Mechanism of Carcinogenesis; p21; CIP1; WAF1; 腫瘍原性

Hepatitis C virus (HCV) infects persistently and causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). To address the effect of persistent infection, the conditional expression system of full-genome HCV in human liver cells was established. Following HCV expression, DNA synthesis of cells was suppressed, cell growth was mainly retarded at G0/G1 phase through apoptosis independent pathway. However, after 48 days passage, cell growth has been recovered to be initial level. In order to clarify the target of HCV, we examined the expression level of growth regulators. The cell growth modification by HCV correlated to the extent of p21WAF1/CIP1 expression and hyperphosphorylation of Rb was induced after 48 days passage. This modification of p21WAF1/CIP1 by HCV was caused at transcriptional level in the p53 independent manner. Thus, HCV could modify the cell cycle checkpoint to accelerate the tomurigenicity of hepatocyte through p21WA1/CIP1.The effect of HCV in vivo was also characterized with HCV-transgenic mice model. Expression of HCV made hepatocytes more resistant to Fas-mediated apoptosis. By using in vitro and in vivo HCV expression model, we further characterized the molecular mechanism of pathogenesis of HCV.

丙型肝炎病毒（HCV）持续感染并引起慢性肝炎、肝硬化和肝细胞癌（HCC）。为解决持续感染对HCV表达的影响，建立了HCV全基因组在人肝细胞中的条件表达系统。HCV表达后，细胞DNA合成受到抑制，细胞生长主要通过凋亡非依赖途径阻滞于G 0/G1期。然而，经过48天的传代，细胞生长已恢复到初始水平。为了阐明HCV的靶点，我们检测了生长调节因子的表达水平。HCV对细胞生长的影响与p21 WAF 1/CIP 1表达的程度相关，并在48天后诱导Rb过度磷酸化。HCV对p21 WAF 1/CIP 1的这种修饰是在转录水平上以非p53依赖的方式引起的。因此，HCV可通过p21 WA 1/CIP 1修饰细胞周期检查点，加速肝细胞的致瘤性。HCV的表达使肝细胞对Fas介导的细胞凋亡更有抵抗力。通过体外和体内HCV表达模型的建立，进一步阐明了HCV致病的分子机制。

项目成果

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