Gender-dependent hepatic alterations in H-ras12V transgenic mice

Background/Aims: Although it has been proposed that Ras and related signal pathways play important roles in hepatocarcinogenesis, appropriate in vivo models are lacking. Methods: Two hepatocellular carcinoma lines were established using pronuclear microinjection techniques to create an insertion of the H-ras12V transgene under the control of the albumin enhancer/promoter. The resulting phenotypes and related molecular events were then examined. Results: Male (but not female) transgenic mice older than 2 months showed hepatic alterations with a high degree of reproducibility, as compared to the wild-type mice. The liver/body-weight ratios were lower for the females than for the males. The transgene-carrying line 28 was investigated extensively with respect to molecular differences between the genders. Male hepatocytes showed higher Ras activity and higher reactive oxygen species (ROS) levels than female hepatocytes. The female hepatocytes showed higher expression levels of p53 and p21^Waf1/Cip1, enhanced cytochrome c release, which correlated with cell cycle arrest, and higher levels of hypodiploid cell formation, as compared to the male hepatocytes. Conclusions: The gender-related differences in molecular responses to activated Ras may have implications for the prevalence of hepatic alterations in males. Our transgenic mice represent a potentially valuable animal model for future investigations.