Association of downregulation of cyclin D1 and of overexpression of cyclin E with p53 mutation, high tumor grade and poor prognosis in hepatocellular carcinoma

Background/Aims: The major regulatory events leading to cell proliferation occur in the G(1) phase of cell cycle, and the deranged expression of G(1) cyclins is related to oncogenesis. In this study, we analyzed the aberrant expressions of cyclins D1 and E, and their role in hepatocellular carcinoma. Methods: We examined paired hepatocellular carcinoma and liver RNAs taken from 71 patients who had been followed for more than 4 years after tumor resection, using reverse transcription-polymerase chain reaction supplemented with Northern blotting and immunohistochemistry. The genetic alterations of the p53 gene were also studied. Results: Downregulation of cyclin D1 mRNA was detected in 29 hepatocellular carcinomas (40.8%), while overexpression was detected in only 4 hepatocellular carcinomas (5.6%). Downregulation of cyclin D1 was associated significantly with large hepatocellular carcinomas (p=0.0006) and poorly differentiated (grades HI-IV) hepatocellular carcinoma (p=0.057), but not seen in any of 15 minute hepatocellular carcinomas (less than or equal to 2.5 cm in size). Cyclin E mRNA was overexpressed in 40 hepatocellular carcinomas, regardless of tumor size. Overexpression of cyclin E was significantly associated with poorly differentiated and invasive hepatocellular carcinoma (p=0.001 and p=0.015, respectively). Downregulation of cyclin D1 and overexpression of cyclin E were significantly associated with the p53 mutation (p=0.023 and p=0.005, respectively). Hepatocellular carcinomas expressing both downregulation of cyclin D1 and overexpression of cyclin E had the worst 4-year survival (p<0.03), and higher frequencies of the p53 mutation (p<0.001), large hepatocellular carcinoma (p<0.001), and invasive tumor (p<0.01). Conclusions: The deranged expressions of G(1) cyclins correlate with the p53 mutation, tumor progression, and tumor biologic behavior of hepatocellular carcinoma. Overexpression of cyclin E occurs early, and downregulation of cyclin D1 late in hepatocellular carcinoma growth.