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，慢性丙型肝炎病毒感染是肝细胞癌发生的主要危险因素。在与丙型肝炎相关的肝细胞癌的发病机制中，病毒是发挥直接作用还是仅仅起到间接作用仍存在争议。我们和其他人利用具有致癌潜力的核心蛋白的转基因小鼠模型进行的研究表明，丙型肝炎病毒直接参与了肝癌的发生，尽管与炎症相关的其他因素也可能起作用。核心蛋白的下游事件被分离为两个组分。其一是在肝脏脂肪变性的癌前阶段，随着包括过氧化氢酶和谷胱甘肽在内的清除系统的激活，活性氧物种(ROS)的产生增加。因此，在没有炎症的情况下，核心蛋白产生的ROS可能是d…的部分原因。肝细胞癌的进一步发展。据估计，ROS的产生源于丙型肝炎病毒感染引起的肝细胞线粒体功能障碍。另一种是细胞内MAPK(JNK)、AP-1、Cyclin D1和CDK4信号级联的改变。这些事件，再加上脂质和糖代谢的改变，将导致持续感染的丙型肝炎患者发生肝细胞癌。我们的结果表明，持续感染的丙型肝炎患者发生肝癌的机制与其他癌症不同。与以结直肠癌为代表的其他恶性肿瘤的发病机制类似，一系列基因异常的积累也可能是肝细胞癌多阶段发展所必需的。然而，被认为具有致癌潜力的丙型肝炎病毒核心蛋白可能允许在肝癌发生过程中跳过多个阶段中的一些阶段。因此，与其他癌症不同的是，感染丙型肝炎病毒可能会在缺乏一套完整的遗传变异的情况下诱发肝细胞癌。这样的情景可以解释慢性丙型肝炎患者发生肝细胞癌的异常高发病率和多中心特性。

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