Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice

Cyclin DI is a known oncogene and a key regulator of cell cycle progression . Amplification of the cyclin DI gene and its overexpression have been asso ciated with aggressive forms of human hepatocellular carcinoma (HCC). In th is study, two independent lines of transgenic mice have been generated that express cyclin DI under the control of the rat liver fatty acid binding pr otein promoter, This transgene specifically directs expression in the liver and the intestines. RNA and protein analysis demonstrated increased expres sion of the cyclin D1 gene product in the liver and bowel when compared wit h wild-type siblings. Both transgenic lines developed progressive liver dis ease. Examination of H&E stained sections of the liver and bowel revealed h yperplastic changes in the liver by 3 months of age, By 6 months of age, tr ansgenic mice had obvious hepatomegaly and histological evidence of dysplas ia in the liver. These early changes were significantly more dramatic in ma le animals when compared with Female animals. By 9 months of age adenomas o f the liver appeared, progressing to HCC over the ensuing 6-month period, B y 15-17 months of age, 87% of male and 69% of female animals had either ade nomatous nodules or HCCs, By 17 months of age, 31% of male and female anima ls had disease that had progressed to HCC, These animals represent a unique and significant new model for the study of human HCC. This study demonstra tes that overexpression of cyclin DI is sufficient to initiate hepatocellul ar carcinogenesis.