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 alpha 6 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 alpha 6 and CD151. The molecular effects of high expression levels of alpha 6 and CD151 in HCC cells were determined using RNA interference and pharmacologic approaches. RESULTS: Overexpression of alpha 6 correlated with poor prognosis of patients with HCC; alpha 6 formed a complex with endogenous CD151 in HCC cells. In cells that expressed high levels of alpha 6 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 alpha 6 or CD151. Cells that expressed high levels of alpha 6 and CD151 underwent the EMT in response to laminin-5, through hyperactivation of phosphatidylinositol- 3-kinase (PI3K), primarily induced via the PI3Kprotein kinase B (Akt)-Snail-phosphatase and tensin homolog feedback pathway. The EMT was reversed by PI3K inhibitors and antibodies against CD151 or alpha 6 in vitro, and was delayed by specific interference with CD151 and alpha 6 in vivo. CONCLUSIONS: High expression levels of CD151 and alpha 6 promote invasiveness of HCC cells. Either of these proteins, or PI3K signaling, might be targets for therapeutics for subgroups of patients with HCC.