alpha 6 beta 1 integrin expression in hepatocarcinoma cells: Regulation and role in cell adhesion and migration

Liver carcinogenesis is associated with striking changes in the integrin re pertoire of hepatocytes, including the overexpression of the laminin and co llagen receptors alpha 1 beta 1 and the de novo induction of the laminin re ceptor alpha 6 beta 1. Our aim was to analyze the role of pro-inflammatory cytokines, interferons and fibrogenic cytokines TGF-beta and FGF2 in the re gulation of the expression of beta 1 integrins by neoplastic hepatocytes. T he 2 human hepatocellular cell lines HepG2 and Hep3B were used as models. I ntegrin expression was assessed by qualitative methods (immunocytochemistry , Western blotting) and semi-quantitative techniques (FACS, cellular ELISA) , before and after stimulation by TNF alpha, IL1-beta, TGF-beta, FGF2, inte rferon gamma and interferon alpha-2b. HepG2 and Hep3B constitutively expres sed alpha 1, alpha 2, alpha 6 and beta 1 chains. A 24 to 48-hr stimulation with pro-inflammatory cytokines, TGF-beta and FGF2 induced a significant in crease in the concentrations of all integrin chains. The maximum induction was registered for beta 1 chain, which presented increases amounting up to 3, 4 and 7 times the control values in the presence of, respectively, TNF a lpha/IL1-beta, TGF-beta and FGF2. Interferons had no direct effect on integ rin expression and partially antagonized the effects of TNF alpha and TGF-b eta. The increased concentrations of integrin chains were associated with a n increased membrane expression of the corresponding dimers and with an inc reased adhesion of stimulated hepatocytes to laminin, which was antagonized by neutralizing anti-beta 1 and anti-alpha 6 antibodies. Finally, anti-alp ha 6 antibody inhibited the migration of HepG2 and Hep3B cells in reconstit uted basement membrane. Our results suggest that the stimulation of alpha 6 beta 1 integrin expression in hepatocarcinoma cells is essential for cell adhesion and migration. Int. J. Cancer, 83:518-525, 1999, (C) 1999 Wiley-Li ss, Inc.