CD151 Amplifies Signaling by Integrin α6β1 to PI3K and Induces the Epithelial–Mesenchymal Transition in HCC Cells

Background & Aims Overexpression of CD151 is associated with poor prognosis for hepatocellular carcinoma (HCC), yet its role in pathogenesis is not known. Methods We analyzed the expression of the integrin subunit α6 by quantitative, real-time polymerase chain reaction and immunoblot analyses of 120 HCC tissue samples; its clinical significance was investigated using tissue microarray (TMAs) analysis of samples from 335 patients with HCC. Immunoprecipitation was used to assess the relationship between α6 and CD151. The molecular effects of high expression levels of α6 and CD151 in HCC cells were determined using RNA interference and pharmacologic approaches. Results Overexpression of α6 correlated with poor prognosis of patients with HCC; α6 formed a complex with endogenous CD151 in HCC cells. In cells that expressed high levels of α6 and CD151, laminin-5 promoted cell spreading by inducing the epithelial–mesenchymal transition (EMT); this effect was not observed in cells that expressed high levels of only α6 or CD151. Cells that expressed high levels of α6 and CD151 underwent the EMT in response to laminin-5, through hyperactivation of phosphatidylinositol-3-kinase (PI3K), primarily induced via the PI3K–protein kinase B (Akt)–Snail–phosphatase and tensin homolog feedback pathway. The EMT was reversed by PI3K inhibitors and antibodies against CD151 or α6 in vitro, and was delayed by specific interference with CD151 and α6 in vivo. Conclusions High expression levels of CD151 and α6 promote invasiveness of HCC cells. Either of these proteins, or PI3K signaling, might be targets for therapeutics for subgroups of patients with HCC.