Kato Takanobu, Miyamoto Michiko, Date Tomoko, Yasui Kotaro, Taya Choji, Yonekawa Hiromichi, Ohue Chiharu, Yagi Shintaro, Seki Ekihiro, Hirano Tadamichi, Fujimoto Jiro, Shirai Tomoyuki, Wakita Takaji
Department of Microbiology, Tokyo Metropolitan Institute for Neuroscience, Fucyu, Tokyo 183-8526, Japan.
Cancer Sci. 2003 Aug;94(8):679-85. doi: 10.1111/j.1349-7006.2003.tb01502.x.
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 (CCl(4)) 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-transgenic littermates; however, after 40 weeks, hepatic adenomas preferentially developed in transgenic mice receiving 20% CCl(4) once weekly. Moreover, HCC was observed in transgenic mice receiving 2 weekly injections of a 20% solution of CCl(4), and was 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 CCl(4) 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 with which to investigate hepatocarcinogenesis.
尽管丙型肝炎病毒（HCV）是肝细胞癌（HCC）的一种众所周知的致病因子，但HCV诱发HCC的机制仍不清楚。为了阐明HCV在肝癌发生中的作用，利用HCV核心转基因小鼠建立了肝细胞损伤模型，该小鼠是通过将HCV核心基因转染到在血清淀粉样P成分启动子控制下的C57BL/6小鼠中培育而成的。18至24个月后，在转基因小鼠中未发现脂肪变性或肝肿瘤。然后，采用不同方案（20%，每周1次；10%，每周2次和20%，每周2次）对转基因小鼠反复给予四氯化碳（CCl₄）后，检测肝细胞损伤程度和肿瘤发生情况。HCV核心转基因小鼠和非转基因同窝小鼠的血清丙氨酸氨基转移酶（ALT）水平没有差异；然而，40周后，每周接受1次20% CCl₄的转基因小鼠优先发生肝腺瘤。此外，在每周接受2次20% CCl₄溶液注射的转基因小鼠中观察到了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发展。然而，在反复给予CCl₄后，HCV核心蛋白促进了转基因小鼠的腺瘤和HCC发展。这些结果表明，导致肝细胞再生率增加的肝毒性增强了HCV感染肝脏中的肝癌发生。此外，这种实验性小鼠模型为研究肝癌发生提供了一种有价值的方法。
