Mutant Hras ^G12V and Kras ^G12D have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice

Background: Mouse hepatocarcinogenesis is associated with mutations in Hras, but infrequently in Kras. The effect on carcinogenesis of developmental age at the time of ras mutation remains unknown. Aim: We sought to compare quantitatively the effects of expressing mutant H- or Kras genes in fetal vs. adult mouse liver. Methods: We established an inducible system of gene expression in mouse liver to define disease pathogenesis associated with activation of oncogene expression. Results: Diffuse expression of either oncogene in fetal or adult hepatocytes caused hepatomegaly. For mutant Hras ^G12V, this phenotype was almost fully reversible and accompanied by apoptosis, indicating that maintenance of hepatomegaly requires continuous Hras ^G12V expression. We also examined the effect of ras expression on growth of transplanted hepatocytes in an in vivo system that allows us to quantify hepatocyte growth effects in both permissive and restrictive hepatic growth environments. Mutant Kras ^G12D had no effect on hepatocyte growth in this system. In contrast, Hras ^G12V induced increased hepatocyte focus growth in quiescent liver, the hallmark of a cell autonomous growth stimulus. Hras ^G12V also increased the fraction of donor hepatocyte foci that displayed extreme growth, a characteristic of preneoplastic lesions. Conclusions: The primary effect of diffuse, whole-liver expression of either mutant ras gene in fetal or adult mouse liver is diffuse and progressive hepatic growth. Hras ^G12V mutation influences hepatocarcinogenesis by conferring cell autonomous growth potential upon foci of expressing cells and by increasing the risk of neoplastic progression. Kras ^G12D does not share these latter carcinogenic effects in mouse liver.