Analysis of Cell Proliferative Activity, p53 Protein Overexpression and Apoptosis in Hepatocellular Carcinoma and Surrounding Nontumorous Liver

Lim, So Dug; Kim, Woo Ho; Jang, Ja June; Yu, Eun Sil

Abstract

BACKGROUND/AIMS
Although the mechanism of hepatocellular carcinogenesis still remains to be clarified, it has been suggested that persistent hepatic necrosis and resultant irregular regeneration might cause genetic mutations, such as activation of protooncogenes, inactivation of tumor suppressor genes and modulation of apoptosis-related genes, finally leading to hepatocellular carcinoma (HCC). To elucidate the role of cell proliferative activity and apoptosis, a major mechanism of cell death, in hepatocellular carcinogenesis, we analyzed expression of proliferation cell nuclear antigen (PCNA), p53 protein and apoptotic cells in HCC and surrounding nonneoplastic hepatic parenchyma.
METHODS
We performed immunohistochemical staining to detect P CAN, p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method for the detection of apoptosis in 52 hepatocellular carcinomas and their adjacent nonneoplastic liver. We scored the expression of PCNA and p53, and apoptotic index by a 5 point scale' 0, 0%,1, 1-25%', 2, 25-50%, 3, 50-75%', 4, >76%, and analyzed the results with other clinicopathologic characteristics.
RESULTS
p53 protein was expressed in 42.3% of the HCC, but was not evident in nonneoplstic liver. P53 overexpression was correlated with the histologic grade of HCC (p<0.05). PCNA labelling indices (LI) of HCC were correlated with those of liver cell dysplasia and normal liver (p<0.05). Leading edges of HCCs showed higher proliferative activity than the central part of HCC. Four cases of HCCs with high TUNEL also showed high proliferative activity. There was no difference of the TUNEL between HCC and surrounding nonneoplastic liver. Expression of p53, PCNA LI and TUNEL had no relationship with clinicopathologic parameters including viral markers, aFP elevation, tumor size and underlying cirrhosis.
CONCLUSION
p53 overexpression in HCC and absence of p53 mutation in nonneoplastic liver indicates the active participation of p53 in hepatocellular carcinogenesis. Invasiveness and metastatic potential appear to be related with the strong expression of PCNA, but apoptosis in HCC has no direct implication in hepatocellular carinogensis.