AIM: To investigate the molecular mechanism of alphafetoprotein (AFP) on regulating the proliferation of human hepatocellular carcinoma cells. METHODS: Alpha-fetoprotein purified from human umbilical blood was added to cultured human hepatocellular carcinoma Bel 7402 cellsin vitro for various treatment periods. The expression of c-fos, c-jun, and N-ras mRNA involved in proliferation and differentiation of cells was analyzed byNorth blot, and the expression of mutative p53 and p21rasproteins was determined by West blot. RESULTS: The results showed that AFP (20 mg/L) stimulated mRNA expression of these oncogenes in Bel 7402 cells. The expression of c-fos mRNA increased by 51.1%, 60.9%, 96.0%, and 25.5% at 2, 6, 12, and 24 h, respectively. Theexpression of c-jun a nd N-ras mRNA reached to the maximum which increased by 81.3% and 59.9% as compared withthe control after 6 h and 24 h incubation with AFP, respectively. West blot assay also demonstrated that AFP promotedthe expression of mutative p53 and p21ras proteins, and the increased rate of those proteins was 13.0%, 39.9%, and 70.9%, as well as 35.2%, 102.6%, and 46.8% at 6, 12, and 24 h, respectively, as compared with the control. Both human serum albumin (the same dosage as AFP) and monoclonalanti-AFP antibody failed to stimulate the expression of these oncogenes, but anti-AFP antibody could block the functions of AFP.CONCLUSION: The data indicate that AFP can stimulate the expression of some oncogenes to enhance the proliferation of human hepatocellular carcinoma Bel 7402 cells.