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

虽然丙型肝炎病毒（HCV）是众所周知的肝细胞癌（HCC）的病原体，但HCV诱导HCC的机制仍不清楚。为了阐明HCV在肝癌发生中的作用，使用HCV核心转基因小鼠建立肝细胞损伤模型，所述HCV核心转基因小鼠使用在血清淀粉样蛋白P组分启动子控制下转染HCV核心基因的C57 BL/6小鼠。18 - 24个月后，转基因小鼠既没有发现脂肪变性，也没有发现肝肿瘤。采用四氯化碳（CCl_4）染毒转基因小鼠，分别以20%：1/周、10%：2/周和20%：2/周的剂量重复染毒，观察肝细胞损伤程度和肿瘤发生情况。血清丙氨酸氨基转移酶（ALT）水平在HCV核心转基因小鼠和非transgeriic同窝小鼠之间没有差异，但是，40周后，每周接受一次20%CCl4的转基因小鼠优先发生肝腺瘤。此外，在接受每周2次注射20%CCl4溶液的转基因小鼠中观察到HCC，而在非转基因对照小鼠中未观察到。总之，在没有肝毒性的情况下，HCV核心蛋白不会促进肝脂肪变性或肿瘤的发展。然而，HCV核心蛋白促进腺瘤和肝癌的发展，在转基因小鼠反复四氯化碳管理。这些结果表明，肝毒性导致肝细胞再生率增加，增强了HCV感染肝脏的肝癌发生。此外，这种实验小鼠模型提供了一种有价值的方法，通过它来研究肝癌的发生。

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.