Toxicological Sciences 56, 297-302 (2000)
Copyright © 2000 by the Society of Toxicology
Correlation between Bcl-2 Overexpression and H-ras Mutation in Naturally Occurring Hepatocellular Proliferative Lesions of the B6C3F1 Mouse
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* Biosafety Research Center, Foods, Drugs and Pesticides, 582–2 Arahama, Shioshinden, Fukude-cho, Iwata-gun, Shizuoka 437-1213, Japan; and
Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52–1 Yada, Shizuoka-shi, Shizuoka 422-8526, Japan
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 hepatocellular proliferative lesions in B6C3F1 mice. Specimens of histologically diagnosed neoplastic or preneoplastic lesions of the liver, obtained from the control mice used for 2-year carcinogenicity studies, were examined by immunohistochemical techniques. All of 25 lesions confirmed to be hepatocellular carcinomas stained positive for the Bcl-2 protein. Three of 12 foci of cellular alterations, as well as 24 of 42 hepatocellular adenomas, stained weakly positive. Bcl-2 protein was expressed to a greater degree in hepatocellular carcinomas as opposed to adenomas and confirmed by Western blot analysis. Seven of 18 hepatocellular adenomas that stained positive for Bcl-2 and three of 16 hepatocellular adenomas that stained negative had a mutation at codon 61 of the H-ras gene. Overexpression of Bcl-2 protein is likely 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 gene may be critical factors in the development of naturally occurring hepatocellular tumors in B6C3F1 mice.
Key Words: Bcl-2; H-ras; B6C3F1 mouse; liver tumor.
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