Overexpression of cyclin E and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas

Mammalian cell cycle progression is regulated by the combined action of cyc lins/cyclin-dependent kinases (CDKs) and CDK inhibitors. Abnormal expressio n as well as interaction of these proteins may result in malignant transfor mation of cells. To further address the role of these cell cycle proteins i n hepatocellular carcinomas. we analyzed the expression of cyclin E and CDK 2. A panel of livers with human hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis were used as a human experimental system. The inbred LEC (Long-Evans with a cinnamon-like coat color) rats were used as an anima l experimental HCC model. Immunohistochemical staining of serial paraffin s ections was performed using antibodies to cyclin E and CDK2. The results sh owed that cyclin E and CDK2 were concurrently overexpressed in hepatocellul ar carcinomas both in human and rat livers. Western blot analysis and CDK2 kinase assay demonstrated expression levels of cyclin E and CDK2 and CDK2 k inase activity, respectively, and both were shown to increase along with th e development of hepatocellular carcinomas. Analysis of the correlation bet ween expression of cyclin E and CDK2 and clinicopathological parameters rev ealed a significant correlation between expression of cyclin E and tumor gr ade (P = 0.013). and PCNA index (P = 0.006) as well as CDK2 expression (P = 0.015). Overexpression of CDK2 tended to be associated with poorly differe ntiated HCCs. The results suggest that overexpression of cyclin E and CDK2 plays an important role in the development of hepatocellular carcinoma. (C) 2001 Elsevier Science B.V. All rights reserved.