Correlation between Bcl-2 overexpression and H-ras mutation in naturally occurring hepatocellular proliferative lesions of the B6C3F1 mouse

The correlation between the mutation at codon 61 of the H-ras gene and the expression of the Bcl-2 protein was investigated in naturally occurring hep atocellular proliferative lesions in B6C3F1 mice. Specimens of histological ly diagnosed neoplastic or preneoplastic lesions of the liver, obtained fro m the control mice used for 2-year carcinogenicity studies, were examined b y immunohistochemical techniques, All of 25 lesions confirmed to be hepatoc ellular carcinomas stained positive for the Bcl-2 protein. Three of 12 foci of cellular alterations, as well as 24 of 42 hepatocellular adenomas, stai ned weakly positive. Bcl-2 protein was expressed to a greater degree in hep atocellular carcinomas as opposed to adenomas and confirmed by Western blot analysis. Seven of 18 hepatocellular adenomas that stained positive for Bc l-2 and three of 16 hepatocellular adenomas that stained negative had a mut ation at codon 61 of the H-ras gene. Overexpression of Bcl-2 protein is lik ely to enhance the malignant turnover of the neoplastic cells, following a mutation at codon 61 of the H-ras gene particularly. These findings suggest that Bcl-2 overexpression and the mutation at codon 61 of the H-ras gem ma y be critical factors in the development of naturally occurring hepatocellu lar tumors in B6C3F1 mice.