Construction and analysis of viral hepatocarcinogenesis model using HCV transgenic mouse model

虽然丙型肝炎病毒是众所周知的肝细胞癌的病原体，但其诱发肝癌的机制尚不清楚。为探讨丙型肝炎病毒在肝细胞癌发生中的作用，用血清淀粉样蛋白P组分启动子控制下的C57BL/6小鼠建立了丙型肝炎病毒核心转基因小鼠肝细胞损伤模型。18-24个月后，转基因小鼠既没有脂肪变性，也没有肝脏肿瘤。然后在转基因小鼠中以不同的方案(20%：1/周、10%：2/周和20%：2/周)重复给予四氯化碳(CCl4)，然后检测肝细胞损伤和肿瘤形成的程度。血清丙氨酸氨基转移酶(ALT)水平在丙型肝炎病毒核心转基因小鼠和非转基因小鼠之间没有差异，然而，40周后，每周服用20%CCL4的转基因小鼠优先发展为肝腺瘤。此外，在每周两次注射20%CCl4溶液的转基因小鼠中，观察到了肝癌，而在非转基因对照小鼠中没有观察到肝癌。总之，在没有肝脏毒性的情况下，丙型肝炎病毒核心蛋白不会促进肝脏脂肪变性或肿瘤的发展。然而，在反复注射CCl4后，丙型肝炎病毒核心蛋白促进了转基因小鼠的腺瘤和肝癌的发展。这些结果表明，肝毒性导致肝细胞再生率增加，增强了丙型肝炎病毒感染肝脏的肝癌发生。此外，这个实验性的小鼠模型为研究肝癌的发生提供了一个有价值的方法。

Although hepatitis C virus (HCV) is a well known causative agent of hepatocellular carcinoma (HCC), the mechanism by which HCV induces HCC remains obscure. To elucidate the role of HCV in hepatocarcinogenesis, a model of hepatocyte injury was established using HCV core transgenic mice, which were developed using C57BL/6 mice transfected with the HCV core gene under control of the serum amyloid P component promoter. After 18 -24 months, neither steatosis nor hepatic tumors were found in transgenic mice. The extent of hepatocyte injury and tumorigenesis were then examined in transgenic mice following repeated administration of carbon tetrachloride (CCl4) using various protocols (20%: 1/week,10%: 2/week and 20%: 2/week). Serum alanine aminotransferase (ALT) levels did not differ among HCV core transgenic mice and non-transgeriic littermates, however, after 40 weeks, hepatic adenomas preferentially developed in transgenic mice receiving 20% CCl4 once weekly. Moreover, HCC was observed in transgenic mice receiving 2 weekly injections of a 20% solution of CCl4,and not observed in the non-transgenic control mice. In conclusion, the HCV core protein did not promote hepatic steatosis or tumor development in the absence of hepatotoxicity. However, the HCV core protein promoted adenoma and HCC development in transgenic mice following repeated CCl4 administration. These results suggest that hepatotoxicity resulting in an increased rate of hepatocyte regeneration enhances hepatocarcinogenesis in HCV infected livers. Furthermore, this experimental mouse model provides a valuable method by which to investigate hepatocarcinogenesis.