Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein

Background/Aims: Chronic infection with hepatitis B virus is a high-risk fa ctor for hepatocellular carcinoma in humans, The HBV X-protein, a multi-fun ctional viral regulator, has been suspected to play a positive role in hepa tocarcinogenesis, as demonstrated by the high incidence of hepatocellular c arcinoma in HBx-expressing transgenic mice, although it is still controvers ial. The aim of this study was to generate transgenic mice expressing the H BV X-gene under authentic promoter control and to test whether the gene pro ducts can cause hepatic tumors. Methods: Three transgenic mouse lines were generated by microinjecting the X-gene construct into hybrid (C57BL/6xDBA) eggs. Gene expression was tested by protein and mRNA analyses. During an observation period of 18 months, m ice were sacrificed and organs subjected to histologic examinations. Results: Grossly defined hepatocellular carcinomas reproducibly were observ ed in mice expressing the X-protein, which were investigated through six ge nerations from the age of 11 to 18 months. Among 14 transgenic mice investi gated from the age of 11 to 18 months, 12 were found to have hepatocellular carcinoma, grossly or microscopically. The lesion of the hepatocellular ca rcinoma disclosed a significant increase in the proliferating cell nuclear antigen in the nuclei, Conclusion: The incidence of hepatocellular carcinoma (86%) in our HBV X tr ansgenic mice may be highly significant, since, except for one case, HBV X- gene transgenic mice produced in other laboratories did not develop liver t umor or any other pathologic phenomena.