Hepatocyte growth factor (HGF) is an important paracrine regulator for liver growth, whereas it inhibits growth of tumor cells including hepatocellular carcinoma. In contrast, transforming growth factor alpha (TGF alpha) is a factor which stimulates hepatocyte growth and causes hepatocellular carcinoma in an autocrine fashion. To determine whether TGF alpha is affected by HGF, we examined the regulation of TGF alpha expression in response to exogenous HGF in HepG2 cells. We first examined TGF alpha mRNA and protein in the presence of HGF and found nearly a 3.6-fold increase in mRNA and a 2.5-fold increase in TGF alpha protein. This induction was dose-dependent and followed delayed kinetics. Nuclear run-on experiments suggested that the mechanism for this induction was an increase in transcription of TGF alpha mRNA. These data suggest that HGF may modulate TGF alpha expression and the interaction of these cytokines may play an important role in liver diseases.