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

大量的流行病学证据表明，慢性丙型肝炎病毒（HCV）感染是HCC发展的主要危险因素。在与HCV相关的HCC发病机制中，病毒是否起直接作用或仅起间接作用仍存在争议。我们等人使用转基因小鼠模型的研究表明，HCV核心蛋白具有致癌潜力，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可能也起作用。核心蛋白的下游事件被分成两个部分。一是在肝脏脂肪变性的肿瘤前阶段，活性氧（ROS）的产生随着清除系统（包括过氧化氢酶和谷胱甘肽）的激活而增加。因此，在核心蛋白没有炎症的情况下，ROS的产生可能在一定程度上促进了HCC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。二是细胞内MAPK （JNK）、AP-1、cyclin D1和CDK4信号级联的改变。这些事件，加上脂质和糖代谢的改变，将导致持续HCV感染的肝细胞癌（HCC）的发展。我们的研究结果表明，持续HCV感染可能存在不同于其他癌症的肝癌发生机制。与以结直肠癌为代表的其他恶性肿瘤的发病机制类似，一组遗传畸变的积累也可能是HCC多阶段发展的必要条件。然而，HCV核心蛋白，其致癌潜力被归因于，可能允许在肝癌发生过程中跳过一些多个阶段。因此，与其他癌症不同的是，在没有一整套基因畸变的情况下，HCV感染可能能够诱导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

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