Altered bcl-2 family expression during non-genotoxic hepatocarcinogenesis in mice

Dysregulation of apoptosis is an important component of multistage hepatoca rcinogenesis. Members of the bcl-2 protein family are important in the regu lation of apoptosis and their expression is altered in several cancers. The objectives of the present study were to determine whether the expression o f members of the bcl-2 protein family are altered in mouse liver during acu te treatment with nongenotoxic carcinogens and throughout non-genotoxic hep atocarcinogenesis, Acute treatment of B6C3F1 mice with phenobarbital result ed in increased levels of bcl-2 and decreased levels of bar protein, while acute treatment with WY-14,643 resulted in increased bcl-2 and BAG-1 protei n in the liver. Following chronic treatment, altered hepatic foci and adeno mas were classified as: small-cell, heterogeneous basophilic lesions (spont aneous or tetrachlorodibenzo-p-dioxin-induced); large-cell, homogeneous bas ophilic lesions (WY-14,643-induced); acidophilic lesions (phenobarbital- or chlordane-induced). Of the small-cell heterogeneous basophilic lesions, 86 % of foci (31/36) and 85% of adenomas (35/41) exhibited increased bcl-2 pro tein levels compared with surrounding normal hepatocytes, whereas only 12.5 % of foci (4/36) and 12% of adenomas (5/41) exhibited increased bcl-X-L lev els. Of the large-cell, homogenous, basophilic lesions, 100% of foci (3/3) and 90% of adenomas (9/10) expressed bcl-2 protein, whereas 100% of foci (3 /3) and 80% of adenomas (8/10) exhibited increased bcl-X-L protein levels c ompared with surrounding normal hepatocytes. Of the acidophilic lesions, th e majority of foci (28/32, 88%) and adenomas (47/50, 94%) expressed increas ed bcl-X-L, whereas increased bcl-2 was observed in only 12.5% of acidophil ic preneoplastic foci (4/32) and 14% of acidophilic adenomas (7/50), Of the carcinomas analyzed, 81% expressed increased bcl-2 (54/67), 78% expressed increased bcl-X-L (52/67) and 69% expressed increased levels of both bcl-2 and bcl-X-L (46/67), Collectively, only 8% of preneoplastic foci, 3% of ade nomas and 1.5% of carcinomas did not express either bcl-2 or bcl-X-L. These results suggest that regulation of apoptotic proteins is altered during no n-genotoxic carcinogenesis in mouse liver. Furthermore, there were both che mical- and lesion-specific aspects of expression of apoptotic proteins duri ng hepatocarcinogenesis in mice.