Reduced p21(WAF1/CIP1)protein expression is predominantly related to altered p53 in hepatocellular carcinomas

To investigate the relationship between the expression of p21(WAF1/ClP1)protein and p53 status and the possible role of the two proteins in hepatocellular carcinomas (HCCs), we examined the expression of p21(WAF1/CIP1)and p53 immunohistochemically in 81 tumours from 65 patients with hepatocellular carcinoma. p21(WAF1/CIP1)protein was absent from 59 of 81 tumours (72.8%), and altered p53 expression was found in 43 (53.1%). p21(WAF1/CIP1)expression was significantly associated with p53 status (P= 0.0008); 38 of 59 tumours lacking p21(WAF1/CIP1)protein were accompanied by altered p53 expression. Further analyses showed that p21(WAF1/CIP1)expression was inversely correlated with p53 expression in hepatitis C virus (HCV)-related HCCs, but not in HBV-related hepatocellular carcinomas and hepatocellular carcinomas without viral infection. All 11 tumours with intrahepatic metastasis showed altered p21(WAF1/CIP1)or p53 expression. In contrast, no intrahepatic metastasis was found in any of the 17 tumours without abnormal expression of either of the two proteins. These results suggest that: (1) different modes of p21(WAF1/CIP1)regulation are involved in HCCs differing in their hepatitis viral infection status, and p21(WAF1/CIP1)expression appears to be predominantly related to altered p53 in HCV-related HCCs; (2) disruption of the p53–p21(WAF1/CIP1)cell- cycle-regulating pathway may contribute to malignant progression of HCC. © 2000 Cancer Research Campaign