Transforming growth factor-beta 1-induced apoptosis is blocked by beta 1-integrin-mediated mitogen-activated protein kinase activation in human hepatoma cells.
Growth factors and extracellular matrices cooperatively regulate cellular behavior. However, the interactions between transforming growth factor-beta 1 (TGF-beta 1) and integrins in hepatic cells are not fully understood. We investigated the effects of beta 1-integrin on TGF-beta 1-regulated growth of hepatoma cells. Human hepatoma cell lines HepG2, Huh7, and Hep3B were stably transfected with beta 1-integrin, and the parental, and mock- and beta 1-integrin-transfected hepatoma cells were treated with TGF-beta 1. Modulation of apoptosis and pathways involved in the process were investigated. TGF-beta 1 suppressed the growth of hepatoma cells, and apoptosis was observed in Hep3B and Huh7. Hepatoma cells transfected with beta 1-integrin were protected from TGF-beta 1-induced apoptosis. Mitogen-activated protein (MAP) kinase inhibitors, PD98059, SB203580, and SP600125, abolished this protective effect of beta 1-integrin, but herbimycin A and wortmannin were ineffective. Hepatoma cells overexpressing beta 1-integrin showed increased activities of MAP kinases, and TGF-beta 1 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 beta 1-integrin provide a strong anti-apoptotic signal during TGF-beta 1-induced apoptosis in human hepatoma cells. Therefore beta 1-integrin-mediated signals may contribute to the development and progression of hepatocellular carcinoma.
Zhang
Hao
H
Division of Hepatology and Metabolism, Department of Internal Medicine, Saga Medical School, Saga University, Saga 849-8501.
Ozaki
Iwata
I
Mizuta
Toshihiko
T
Yoshimura
Toru
T
Matsuhashi
Sachiko
S
Eguchi
Yuichiro
Y
Yasutake
Tsutomu
T
Hisatomi
Akitaka
A
Sakai
Takahiro
T
Yamamoto
Kyosuke
K
D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D016326:Extracellular Matrix Proteins; D019012:Integrin beta1; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020928:Mitogen-Activated Protein Kinases