Mechanism of beta 1-integrin-mediated hepatoma cell growth involves p27 and S-phase kinase-associated protein 2.
Although cooperative interactions between growth factors and integrins, cell surface receptors for extracellular matrices (ECM), have been reported, little is known about the interaction between hepatocyte growth factor (HGF) and integrin in hepatoma cells. We investigated the effects and mechanisms of integrin on the proliferation of hepatoma cells regulated by HGF. Human HepG2 hepatoma cells stably transfected with beta 1-integrin were treated with HGF and compared with parental and mock-transfected control cells. Cell proliferation and expression of cyclin-dependent kinase (Cdk) inhibitors and S-phase kinase-associated protein 2 (Skp2), were investigated. HGF dose-dependently suppressed the proliferation of parental and mock-transfected HepG2 cells. However, cells overexpressing beta 1-integrin exhibited increased proliferation in response to HGF. Although HGF increased p27 and decreased Skp2 expression in the parental and mock-transfected cells, the p27 and Skp2 levels in cells overexpressing beta 1-integrin were not altered by HGF. Interestingly, HepG2 cells overexpressing beta 1-integrin showed increased Skp2 expression. Furthermore, HGF did not reduce the proliferation of HepG2 cells transfected with antisense p27 or sense Skp2. Thus, HGF suppresses HepG2 cell proliferation by directly increasing p27 expression and indirectly decreasing Skp2 expression, and beta 1-integrin modulates the responsiveness of hepatoma cells to HGF via a p27-dependent manner by increasing Skp2. In conclusion, these results strongly suggest that integrin-mediated signals from the ECM can modulate growth factor-mediated signals in hepatoma cells, and may contribute to the growth of hepatocellular carcinomas.
Zhang
Hao
H
Division of Hepatology and Metabolism, Department of Internal Medicine, Saga Medical School, Nabeshima, Saga, Japan.
Ozaki
Iwata
I
Mizuta
Toshihiko
T
Yoshimura
Tohru
T
Matsuhashi
Sachiko
S
Hisatomi
Akitaka
A
Tadano
Jutaro
J
Sakai
Takahiro
T
Yamamoto
Kyosuke
K
D006528:Carcinoma, Hepatocellular; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016373:DNA, Antisense; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms; D008164:Luminescent Proteins / Q000235:genetics; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D016373:DNA, Antisense; D039001:Integrin alpha Chains; D019012:Integrin beta1; D008164:Luminescent Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017228:Hepatocyte Growth Factor