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Functional abnormality in the mitochondria and pathogenesis of chronic hepatitis C: relation to hepatocellular carcinoma

线粒体功能异常和慢性丙型肝炎的发病机制：与肝细胞癌的关系

基本信息

批准号：
15390226
负责人：
KOIKE Kazuhiko
金额：
$ 9.6万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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-15390226/
关键词：
ROS hepatitis C virus mitochondrion core protein proteomics electron transfer system hepatocarcinogenesis transgenic mouse

项目摘要

Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis C virus (HCV) poses a major risk toward development of HCC. In the pathogenesis of HCC associated with HCV, it remains controversial whether the virus plays a direct role or merely serves for an indirect role. The studies using transgenic mouse models by us and others, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with inflammation may play a role, as well.The downstream events of the core protein are segregated into two components. One is the augmented production of reactive oxygen species (ROS) along with the activation of scavenging system including catalase and GSH in the putative preneoplastic stage with steatosis in the liver. Thus, ROS production in the absence of inflammation by the core protein may partly contribute to the d … More evelopment of HCC. The generation of ROS is estimated to originate from mitochondrial dysfunction in hepatocytes by HCV infection. The other is the alteration of intracellular signaling cascade of MAPK (JNK), AP-1, cyclin D1 and CDK4. These events, combined with alterations in lipid and glucose metabolism, would lead to the development of hepatocellular carcinoma (HCC) in persistent HCV infection.Our results suggest that there would be a mechanism for hepatocarcinogenesis in persistent HCV infection that is distinct from those for the other cancers. Similar to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multi-stage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain an unusually high incidence and multicentric nature of HCC developing in chronic hepatitis C. Less

压倒性的流行病学证据表明，慢性丙型肝炎病毒（HCV）感染对肝癌的发展构成了主要风险。在与HCV相关的HCC的发病机制中，病毒是否起直接作用或仅起间接作用仍然存在争议。我们和其他人使用转基因小鼠模型进行的研究表明，HCV的核心蛋白具有致癌潜力，这表明HCV直接参与肝癌的发生，尽管其他因素如与炎症相关的持续细胞死亡和再生也可能发挥作用。核心蛋白的下游事件分为两个部分。一个是活性氧（ROS）的产生增加沿着清除系统的激活，包括过氧化氢酶和GSH在假定的肿瘤前阶段与脂肪变性的肝脏。因此，在没有炎症反应的情况下，核心蛋白产生的ROS可能部分促进了炎症反应的发生。 ...更多信息肝癌的发展据估计，ROS的产生源于HCV感染引起的肝细胞线粒体功能障碍。另一个是MAPK（JNK）、AP-1、cyclin D1和CDK 4等细胞内信号通路的改变。这些事件，结合脂质和葡萄糖代谢的改变，将导致肝细胞癌（HCC）的持续HCV感染的发展。我们的研究结果表明，将有一个在持续HCV感染的肝癌的发生机制，是不同于那些为其他癌症。与以结直肠癌为代表的其他恶性肿瘤的发病机制相似，一组遗传畸变的积累也可能是HCC多阶段发展所必需的。然而，丙型肝炎病毒核心蛋白，其中一个致癌潜力归因于，可能会允许一些跳过肝癌发生的多个阶段。因此，与其他癌症不同的是，HCV感染可能能够在缺乏一套完整的遗传畸变的情况下诱导HCC。这种情况可以解释慢性丙型肝炎中HCC的异常高发病率和多中心性。少