Clinical implications of deregulated CDK4 and Cyclin D1 expression in patients with human hepatocellular carcinoma

Abstract

Deregulated cell cycle can contribute to the unscheduled proliferation in cancer cells. Overexpression of cell cycle regulators CDK4 and Cyclin D1 has been reported in many cancers. The aim of this study is to determine the clinical implications of CDK4 and Cyclin D1 in hepatocellular carcinoma (HCC). The levels of mRNA and protein were analyzed by quantitative real-time RT-PCR and immunohistochemistry, respectively, in 59 paired HCC and the neighboring noncancer tissues. The relationship between CDK4 and Cyclin D1 expression, clinicopathological parameters, and prognosis was investigated. Our data demonstrated that the mRNA level of CDK4 was up-regulated (p = 0.019), while that of Cyclin D1 was down-regulated (p = 0.002), in HCC. Immunohistochemical data confirmed that CDK4 protein was increased in 73 % and Cyclin D1 protein was decreased in 66 % of HCC samples. Overexpression of CDK4 was correlated with HBV (p = 0.054, borderline significant), tumor size (p = 0.014), and stage (p = 0.010). The Kaplan-Meier survival curves showed that high CDK4 was correlated with a poor survival rate (I vs. II, p < 0.001; I vs. III, p < 0.001). Univariate analysis showed that tumor size (p = 0.002), stage (p = 0.021), and high CDK4 score (I vs. II-III, p < 0.001) were significant prognostic factors. Multivariate analysis showed that tumor size (p = 0.007) and high CDK4 score (I vs. II-III, p < 0.001) were independent factors for overall survival of HCC. The expression of Cyclin D1 was not correlated with CDK4 expression, tumor grades, survival rate, and any clinicopathological parameters. CDK4 could provide a clinical prognostic marker for HCC progression.