Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma.

Transforming growth factor-alpha (TGF-alpha) is a potent mitogen of normal and neoplastic hepatocytes. In addition, TGF-alpha has been reported to play a pivotal role in hepatocarcinogenesis. To evaluate the significance of TGF-alpha in chronic liver diseases and hepatocellular carcinoma, we examined serum TGF-alpha, and expression of TGF-alpha, epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) mRNA in liver tissues. Thirty-five patients with chronic hepatitis (CH), 33 with liver cirrhosis (LC), 55 with hepatocellular carcinoma (HCC) and 53 normal controls (C) were enrolled in this study. Serum TGF-alpha levels were measured by an enzyme-linked immunosorbent assay. Expression of TGF-alpha, EGFR, PCNA and beta-actin mRNA in liver tissues were examined by reverse transcription polymerase chain reaction. Serum TGF-alpha levels in C, CH, LC and HCC were 5.6+/-2.1, 33.2+/-8.3, 404.0+/-173.0 and 100.3+/-39.2 pg/ml, respectively. Serum TGF-alpha level in LC was higher than in other diseases (p<0.01, compared to CH, HCC and C, respectively). Serum TGF-alpha levels exhibited a significant positive correlation with total bilirubin, ICGR15 and Pugh score (p<0.01, p<0.01 and p<0.05, respectively), and increased in parallel with severity of disease according to Child classification. Although the ratios of TGF-alpha, EGFR and PCNA mRNA to beta-actin mRNA were not significantly different among the diseases, the TGF-alpha/beta-actin ratio correlated with EGFR/beta-actin and PCNA/beta-actin ratios (p<0.001 and p<0.0001, respectively), and EGFR/beta-actin ratio was related to PCNA/beta-actin ratio in all patients, especially with HCC. The results of the present study suggest that serum TGF-alpha levels are closely related to severity of liver dysfunction, and that hepatic expression of TGF-alpha and EGFR correlates with proliferation of normal and neoplastic hepatocytes.