Koike Kazuhiko
Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S108-11. doi: 10.1111/j.1440-1746.2006.04669.x.
Persistent infection with hepatitis C virus (HCV) is a major risk factor for development of hepatocellular carcinoma (HCC). However, it remains controversial in the pathogenesis of HCC associated with HCV as to whether the virus plays a direct or an indirect role. The studies using transgenic mouse models, 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 would also play a role. The downstream events of the core protein are segregated into two components. One is the augmented production of oxidative stress along with the activation of scavenging system, including catalase and glutathione, in the putative pre-neoplastic stage with steatosis in the liver. Thus, oxidative stress production in the absence of inflammation by the core protein would partly contribute to the development of HCC. The generation of oxidative stress is estimated to originate from mitochondrial dysfunction in hepatocytes by HCV infection. The other component is the alteration of intracellular signaling cascade of mitogen-activated protein kinase and activating factor (AP)-1, leading to the activation of cell cycle control. The combination of these pathways, collective with HCV-associated alterations in lipid and glucose metabolism, would lead to the frequent development of HCC in persistent HCV infection. These 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 cancers, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HCV core protein, to which an oncogenic potential is ascribed, may allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore unlike for other cancers, HCV infection may be able to cause HCC in the absence of a complete set of genetic aberrations. Such a scenario, 'non-Vogelstein-type' carcinogenesis, would explain the rare feature of hepatocarcinogenesis in HCV infection, the extraordinarily high incidence and the multicentric nature of HCC development.
丙型肝炎病毒（HCV）持续感染是肝细胞癌（HCC）发生的主要危险因素。然而，在与HCV相关的HCC发病机制中，关于该病毒是起直接作用还是间接作用仍存在争议。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，这表明HCV直接参与肝癌发生，尽管其他因素如与炎症相关的持续细胞死亡和再生也会起作用。核心蛋白的下游事件分为两个部分。一是在肝脏脂肪变性的假定癌前阶段，随着包括过氧化氢酶和谷胱甘肽在内的清除系统的激活，氧化应激产生增加。因此，核心蛋白在无炎症情况下产生的氧化应激将部分促成HCC的发生。氧化应激的产生估计源于HCV感染导致的肝细胞线粒体功能障碍。另一个部分是丝裂原活化蛋白激酶和激活因子（AP）-1的细胞内信号级联改变，导致细胞周期调控激活。这些途径与HCV相关的脂质和葡萄糖代谢改变共同作用，将导致持续HCV感染中HCC的频繁发生。这些结果表明，持续HCV感染中存在一种不同于其他癌症的肝癌发生机制。与其他癌症的发病机制类似，一组基因畸变积累对于HCC的多阶段发展可能也是必要的。然而，具有致癌潜力的HCV核心蛋白可能使肝癌发生的多个步骤中的一些得以跳过。因此，与其他癌症不同，HCV感染可能在没有完整的基因畸变集的情况下导致HCC。这种“非沃格尔斯坦型”致癌情况将解释HCV感染中肝癌发生的罕见特征、极高的发病率和HCC发展的多中心性质。
