High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma.

ABSTRACT

BACKGROUND: It has been suggested that p300 participates in the regulation of a wide range of cell biological processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear. METHODS: In this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. RESULTS: Up-regulated expression of p300 mRNA and protein was observed in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were positively stained. High expression of p300 was examined in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival analysis, a significant association between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate analysis (P = 0.021). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001). CONCLUSIONS: Our findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examined by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathologic prognostic model may become a useful tool for identifying HCC patients with different clinical outcomes.