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

丙型肝炎感染和增殖物激活受体α保护(PPAα)在肝细胞癌发生中的作用

基本信息

批准号：
15590633
负责人：
KIYOSAWA Kendo
金额：
$ 2.24万
依托单位：
Shinshu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590633/
关键词：
hepatitis C virus (HCV)HCV core protein PPARα steatosis hepatocellular carcinoma (HCC)PPAR-α

项目摘要

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.

丙型肝炎病毒（HCV）的持续感染可导致肝细胞癌（HCC）的高风险。丙型肝炎病毒核心蛋白（HVB core protein）在小鼠体内的表达可引起肝脂肪变性和肝癌，但不引起肝炎，在HCV相关的肝癌发生中起重要作用。为了阐明HCV核心蛋白是否改变体内与肝脂肪变性和HCC相关的因子的表达，研究了包括癌基因产物、循环调节因子和脂肪酸代谢酶在内的蛋白质的表达。在HCV核心蛋白转基因小鼠中，由过氧化物酶体增殖物激活受体α（peroxisome proliferators-activated receptor α，PPAR α）激活所诱导的多种蛋白表达同时增加，并呈年龄依赖性。在这些小鼠中，核PPAR α发生稳定和活化，可能是由于核游离脂肪酸、内源性PPAR激活因子增加以及与HCV核心蛋白的相互作用。PPAR α的持续和异质性激活似乎扰乱了肝细胞增殖/清除的稳态，导致在肝脏的分散区域中出现异常肝细胞的外壳年龄依赖性外观，过度表达PPAR α或细胞周期蛋白D1。这些异常的肝细胞增殖并倾向于形成多中心簇。这些现象与在用非遗传毒性致癌物（如贝特类）处理的啮齿动物中观察到的完全不同。这些结果首次表明，持续和异质性激活的过氧化物酶体增殖物激活受体α可能有助于由HCV感染引起的年龄依赖性和多中心的肝癌发生。