Sustained overexpression of FoxM1B which increases liver regenerative capacity may have minimal effects on hepatocellular carcinoma development

5056 FoxM1B is a member of the Forkhead box (Fox) transcription factor family whose members play important roles in regulating embryogenesis, cellular proliferation, cellular differentiation and longevity. Expression of FoxM1B correlates with cell proliferation; it is present in rapidly dividing embryonic tissues but is poorly expressed in nonproliferating, differentiated adult tissues. In aged, adult mice, increased hepatic expression of FoxM1B accelerates hepatocyte proliferation after partial hepatectomy, while in hepatocytes in intact liver the transgenic protein is inactive and has no effect on proliferation. This has lead to the suggestion that artificial enrichment of FoxM1B in the liver may be feasible as a gene therapy approach to treatment of liver dysfunction due to aging. To investigate the influence of FoxM1B on liver tumor formation we examined the effect of sustained enrichment of FoxM1B in the hepatocytes of mice treated with a diethylnitrosamine(DEN)/phenobarbital tumor induction protocol. Transgenic enrichment of FoxM1B in hepatocytes did not increase the proliferation rate in normal liver tissue even when the protein was localized to the nucleus. However, it did cause an increase in the proliferation rate and size of preneoplastic and early neoplastic lesions though having no effect on the total numbers of these lesions. As tumors progressed to hepatocellular carcinomas the additional transgenic FoxM1B protein had no effect on cell proliferation, and there was no increase in tumor burden compared to wild type animals. This suggests that the artificial enrichment of FoxM1B in the liver may not be tumorigenic in that organ.