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.

Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma

“…In other HCC cell lines, TGF-b1 induced apoptosis of Hep3B but not of HepG2 cells (Jang et al, 2002;Zhang et al, 2004). We have observed that PDCD4 expression was upregulated in Hep3B but rarely in HepG2 cells by TGF-b1 treatment (unpublished data).…”

New therapies for hepatocellular carcinoma

“…The resulting abnormal combination of ECM ligands and integrin receptors has been proposed to play a role in liver tumor development and metastasis (Carloni et al, 2001;Nejjari et al, 2002;Yang et al, 2003;Zhang et al, 2003). In particular, overexpression of integrin b1 in human HCC cells has been demonstrated to enhance cell proliferation, survial, migratory capacity and resistance to chemotherapy (Carloni et al, 2001;Zhang et al, 2002Zhang et al, , 2003Zhang et al, , 2004. Similarly, induction of FAK gene expression has been observed in human HCC, and elevated FAK levels seem to correlate with a more aggressive tumor behavior (Itoh et al, 2004;Fujii et al, 2004).…”

Integrin signalling adaptors: not only figurants in the cancer story

“…Yet, paradoxically, cancer cells elicit mechanisms that subvert the tumour suppressing functions of TGF-β, and in doing so, confer oncogenic and metastatic activities upon this multifunctional cytokine 69,70 . In epithelial cells, integrin 1 suppresses apoptosis and growth inhibition induced by TGF 71 . In this context p130CAS has been shown to be a crucial player by binding to SMAD3, and preventing its phosphorylation by TGF receptor.…”