ANALYSIS OF TRANSFORMING-GROWTH-FACTOR (TGF)-ALPHA EPIDERMAL GROWTH-FACTOR RECEPTOR, HEPATOCYTE GROWTH-FACTOR C-MET, TGF-BETA RECEPTOR-TYPE-II, AND P53 EXPRESSION IN HUMAN HEPATOCELLULAR CARCINOMAS

Experimental data suggest that dysregulation of growth factors and the cognate receptors may play an important role in hepatocarcinogenesis. The objective of the present study was to characterize the expression of two hepatotrophic growth factor/receptor systems [transforming gro wth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) and hepatocyte growth factor/c-met receptor (HGF/c-met)], both of which a re implicated in the development of human liver tumors. In addition, w e have analyzed the expression of transforming growth factor-beta rece ptor type II (TGF-beta-RII) and p53, genes associated with growth inhi bition and tumor suppression, respectively. Surgical biopsy specimens from 86 human hepatocellular carcinomas were analyzed. TGF-alpha was o verexpressed in 17%, equally expressed in 21%, and down-regulated in 6 2% of the hepatocellular carcinomas when compared to the surrounding h epatic tissue. No major changes were found with EGFR expression. HGF w as overexpressed in 33% and down-regulated in 21% of the tumors. The c -met receptor was overexpressed in 20%, equally expressed in 48%, and down-regulated in 32% of the neoplasms. In contrast, TGF-beta-RII was overexpressed in only 8%, equal in 42%, and down-regulated in 50% of t umors. Nuclear staining of p53, indicative of a mutation(s), was obser ved in the great majority of the tumors (80%), whereas no nuclear p53 was detected in peritumoral tissues. Interestingly, simultaneous down- regulation of c-met and TGF-beta-RII was observed in 23% of the hepato cellular carcinomas, 85% of which also showed nuclear p53 staining. Ta ken together, our data suggest that down-regulation of c-met and TGF-b eta-RII may, together with p53 mutations, play a significant role in h uman liver carcinogenesis.