CELL-CYCLE REGULATORS AND HUMAN HEPATOCARCINOGENESIS

G1 phase progression of mammalian cells is mainly controlled by the cy clin-cyclin-dependent kinase (CDK)-CDK inhibitor-retinoblastoma protei n (pRb) regulatory pathway. Cell cycle regulators controlling G1 phase progression are frequently involved in the carcinogenesis of many hum an cancer types. In hepatocellular carcinoma (HCC) the CDK inhibitor p 16(INK4) is predominantly inactivated by post-transcriptional regulati on and p16(INK4) inactivation participates in the early-stage of hepat ocarcinogenesis and in disease progression. Reduced p21(WAF/CIP1) expr ession, which is associated mainly with p53 gene mutation in HCCs, con tributes to hepatocarcinogenesis. Reduced p27(Kip1) expression is also frequently involved in HCC. The CDK inhibitors p16(INK4), p21(WAF1/CI P1) and p27(Kip1) independently affected and a change in the expressio n of one or more of these inhibitors contributes to carcinogenesis of the majority (nearly 90%) of HCCs. Cyclin D1 amplification and overexp ression play a role in the carcinogenesis of a subset (11-13%) of HCCs . Disruption of the regulatory system controlling G1 phase progression is a common event in human hepatocarcinogenesis. Further studies syst ematically analyzing the major regulators controlling G1 phase progres sion in a large cohort of HCCs will strengthen our understanding of th e molecular mechanism underlying human hepatocarcinogenesis. Correctin g alterations that have occurred in the G1 phase regulatory machinery may provide a novel weapon to treat and prevent HCC.