Mechanism of β1–Integrin-Mediated Hepatoma Cell Growth Involves P27 and S–Phase Kinase-Associated Protein 2

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Abstract
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 β1–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 β1–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 β1–integrin were not altered by HGF. Interestingly, HepG2 cells overexpressing β1–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 β1–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.