Human Cancer Biology Novel Role of MDA-9/Syntenin in Regulating Urothelial Cell Proliferation by Modulating EGFR Signaling

Purpose:Urothelial cell carcinoma (UCC) rapidly progresses from superficial tomuscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of themetastasis-associated geneMDA-9/Syntenin inUCCprogression. ExperimentalDesign: Expression pattern ofMDA-9/Synteninwas examined in 44 primaryUCC and the impact of its overexpression and knockdown was examined in multiple cells lines and key findings were validated in primary tumors. Results: Significantly higher (P 1⁄4 0.002–0.003) expression of MDA-9/Syntenin was observed in 64% (28 of 44) of primary tumors and an association was evident with stage (P 1⁄4 0.01), grade (P 1⁄4 0.03), and invasion status (P 1⁄4 0.02). MDA-9/Syntenin overexpression in nontumorigenic HUC1 cells increased proliferation (P 1⁄4 0.0012), invasion (P 1⁄4 0.0001), and EGF receptor (EGFR), AKT, phosphoinositide 3-kinase (PI3K), and c-Src expression. Alteration of b-catenin, E-cadherin, vimentin, claudin-1, ZO-1, and T-cell factor-4 (TCF4) expression was also observed. MDA-9/Syntenin knockdown in three UCC cell lines reversed phenotypic and molecular changes observed in the HUC1 cells and reduced in vivometastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and colocalization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage (P 1⁄4 0.04, EGFR; P 1⁄4 0.01, AKT). A correlation between MDA-9/Syntenin:b-catenin coexpression with stage (P 1⁄4 0.03) and invasion (P 1⁄4 0.04) was also evident. Conclusions: Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring, and therapeutic strategies for managing UCC. Clin Cancer Res; 19(17); 4621–33. 2013 AACR.