p21/WAF1, p53 and PCNA expression and p53 mutation status in hepatocellular carcinoma

The cyclin-dependent kinase inhibitor p21/WAFI is regulated by p53-dependent and p53-independent pathways. In addition, p21/WAFI binds with proliferating cell nuclear antigen (PCNA) and inhibits the action of PCNA. To investi gate the possible role of p21/WAFI in human hepatocellular carcinomas (HCCs), we examined the expression of p21/WAFI and its relation with PCNA and p53 expression in 97 surgically resected HCCs by immunohistochemistry and with the mutation status of p53 in 26 HCCs. p53 mutation status was examined by direct DNA sequencing using 3 sets of primers covering exons 5-9. Six of the 26 tumors showed p53 point mutations and only 33% of these HCCs demonstrated p21/WAFI expression. In contrast, 75% of HCCs without p53 mutations showed p21/WAFI expression. Of all 97 HCCs, p21/WAFI expression was significantly higher in the tumors than in corresponding non-tumorous liver. When the tumors were stratified into 2 groups by the median tumor p21/WAFI score, those with higher expression were found to have a lower incidence of multiple tumor nodules (p = 0.008) and tumor microsatellite formation (p = 0.050), The tumor p21/WAFI score was positively associated with tumor PCNA expression (p = 0.036) but not with tumor p53 expression. Thus, in HCC, expression of p21/WAFI is in part dependent on p53 status, but a p53-independent pathway also plays a significant role in the regulation of p21/WAFI expression. High p21/WAFI expression is significantly associated with solitary tumor nodules and, to a lesser extent, tumor microsatellites but may not be enough to suppress tumor progression. Int. J. Cancer (Pred. Oncol.) 79:424-428, 1998. (C) 1998 Wiley-Liss, Inc.