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）的持续感染会导致肝细胞癌（HCC）的高风险。丙型肝炎病毒核心蛋白（HVB核心蛋白）在与HCV相关的肝癌发生中起着重要作用，因为它在小鼠中的表达会引起肝脂肪变性和HCC，而无需肝炎。为了阐明HCV核心蛋白是否改变了与体内肝脂肪变性和HCC相关的因子的表达，研究了包括癌细胞产品在内的蛋白质的表达，销售周期调节剂和脂肪酸 - 代谢酶的表达。在HCV核心蛋白质转基因小鼠中，过氧组增生剂激活受体α（PPARα）的激活诱导了许多蛋白的表达。在这些小鼠中，发生核PPARα的稳定和激活可能是由于核无核脂肪酸，内源性PPAR驱动器的增加以及与HCV核心蛋白的相互作用所致。 PPAR A的持续性和异质激活似乎干扰了肝细胞增殖/去除中的稳态，从而导致肝脏散射区域中的外壳年龄依赖性肝细胞，过表达PPARα或周期性D1的外观。这些异常的肝细胞增殖并倾向于形成多中心簇。这些现象与在啮齿动物中观察到的那些现象完全不同，而啮齿动物（如纤维化）等现象。这些结果提供了第一个建议，即PPARα的持续和异源激活可以导致HCV感染引起的年龄依赖性和多中心肝癌发生。