Disruption of p53-p21/WAF1 cell cycle pathway contributes to progression and worse clinical outcome of hepatocellular carcinoma.

Abstract

p53-p21/WAF1 cell cycle pathway plays an important role in growth control, and the inappropriate deregulation of this pathway has been implicated in carcinogenesis. Although the role of p53 in hepatocellular carcinoma (HCC) has been suggested, its exact molecular mechanism in relation to its down-stream gene p21/WAF1 remains unclear. To investigate the relationship between the expression of p53 and p21/WAF1 and the possible roles of the 2 proteins in HCC, we examined the intracellular expression of p53, p21/WAF1 and PCNA immunohistochemically, together with apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay in 35 clinical tissue specimens. The correlation between the clinicopathologic parameters and the intracellular gene expression were analyzed. The results showed that p53 over-expression is a reliable marker for mutational modulation of p53 function. p53 was negatively correlated with p21/WAF1 in hepatitis B virus-related HCC (p=0.024, r=-0.432). Patients with a high p53 expression had a significantly higher Edmondson grading (12/21 vs 13/14, p=0.024) and larger tumor size (10 vs 6 cm, p=0.029). Patients with higher p53 expression had shorter disease-free survival (4 vs 19 months, p=0.0131) and overall survival (11 vs 42 months, p=0.0031). Intracellular expression of p21/WAF1 was positively correlated to proliferating cell nuclear antigen (p=0.001, r=0.776) and apoptosis (p=0.003, r=0.639). Our findings suggest that disruption of p53-p21/WAF1 cell cycle pathways contributes to tumor progression and worse clinical outcome of HCC.