Transforming growth factor-β1-induced apoptosis is blocked by β1-integrin-mediated mitogen-activated protein kinase activation in human hepatoma cells

Abstract

Growth factors and extracellular matrices cooperatively regulate cellular behavior. However, the interactions between transforming growth factor-β1 (TGF-β1) and integrins in hepatic cells are not fully understood. We investigated the effects of β1-integrin on TGF-β1-regulated growth of hepatoma cells. Human hepatoma cell lines HepG2, Huh7, and Hep3B were stably transfected with β1-integrin, and the parental, and mock- and β1-integrin-transfected hepatoma cells were treated with TGF-β1. Modulation of apoptosis and pathways involved in the process were investigated. TGF-β1 suppressed the growth of hepatoma cells, and apoptosis was observed in Hep3B and Huh7. Hepatoma cells transfected with β1-integrin were protected from TGF-β1-induced apoptosis. Mitogen-activated protein (MAP) kinase inhibitors, PD98059, SB203580, and SP600125, abolished this protective effect of β1-integrin, but herbimycin A and wortmannin were ineffective. Hepatoma cells overexpressing β1-integrin showed increased activities of MAP kinases, and TGF-β1 induced sustained activation of MAP kinases in these cells, but only transient activation in mock-transfected cells. These data suggest that MAP kinases activated by β1-integrin provide a strong anti-apoptotic signal during TGF-β1-induced apoptosis in human hepatoma cells. Therefore β1-integrin-mediated signals may contribute to the development and progression of hepatocellular carcinoma.