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  • Transmembrane-Bound IL-15-Promoted Epithelial-Mesenchymal Transition in Renal Cancer Cells Requires the Src-Dependent Akt/GSK-3β/β-Catenin Pathway.

Transmembrane-Bound IL-15-Promoted Epithelial-Mesenchymal Transition in Renal Cancer Cells Requires the Src-Dependent Akt/GSK-3β/β-Catenin Pathway.

Neoplasia (New York, N.Y.) (2015-05-31)
Huaqin Yuan, Xiaoxin Meng, Wenjie Guo, Peifen Cai, Wanshuai Li, Qian Li, Weicheng Wang, Yang Sun, Qiang Xu, Yanhong Gu
ABSTRACT

Intrarenal interleukin-15 (IL-15) plays a major role controlling epithelial survival and polarization both in physiological and pathologic conditions. Herein, we confirmed that human renal cell carcinomas (RCCs) express a membrane-bound IL-15 isoform displaying an unusual molecular weight of 27 kDa. Its stimulation with soluble IL-15 receptor α chain (s-IL-15Rα) triggers epithelial-mesenchymal transition (EMT) process as shown by the down-regulation of E-cadherin and zona occludens 1 and the up-regulation of vimentin and N-cadherin and promotes the migratory and invasive properties of RCC. S-IL-15Rα treatment triggered the Src/PI3K/Akt/GSK-3β pathway and promoted β-catenin nuclei translocation. Deactivation of this pathway by using Src-specific inhibitor PP2, PI3K inhibitor LY294002, and AKT inhibitor MK2206 hampered β-catenin nuclei translocation and suppressed EMT, migration, and invasion of RCC. S-IL-15Rα treatment also enhanced Src-dependent phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (Erk1/2). FAK knockdown significantly decreased the migration and invasion of RCC, which suggest that Src-FAK signaling was involved in s-IL-15Rα-favored migration and invasion of RCC. At the same time, inhibitors of Erk1/2 also significantly decreased the migration and invasion of RCC but could not reverse s-IL-15Rα-induced EMT. Taken together, our results reveal that Src-dependent PI3K/Akt/GSK3b/β-catenin pathway is required for s-IL-15Ra-dependent induction of EMT in RCC, while Src-FAK and Src-Erk1/2 signaling were involved in s-IL-15Rα-promoted migration and invasion properties of RCC. Our study provides a better understanding of IL-15 signaling in RCC tumor progression, which may lead to novel targeted therapies and provide some suggestions when using IL-15 in clinic.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-IL15 antibody produced in mouse, clone 1G3, purified immunoglobulin, buffered aqueous solution
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Monoclonal Anti-IL15 antibody produced in mouse, clone 2H7, purified immunoglobulin, buffered aqueous solution
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Monoclonal Anti-IL15 antibody produced in mouse, clone 3A3, purified immunoglobulin, buffered aqueous solution
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Monoclonal Anti-IL15, (C-terminal) antibody produced in mouse, clone 2F6, purified immunoglobulin, buffered aqueous solution
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IL-15 human, Animal-component free, recombinant, expressed in E. coli, ≥98% (SDS-PAGE), ≥98% (HPLC), suitable for cell culture
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Interleukin-15 human, >97% (SDS-PAGE), recombinant, expressed in E. coli, lyophilized powder, suitable for cell culture
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Anti-IL15 antibody produced in goat, affinity isolated antibody, buffered aqueous solution