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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.

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.

SUBMITTER: Yuan H

PROVIDER: S-EPMC4468369 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD58-expressing tumor cell is implicated in development of various cancers. The present study aimed to reveal the functional significance of CD58 in HCC progression and the underlying mechanisms.MethodsImmunohistochemical staining (IHC), and western blotting were used to detect the expression of CD58 in HCC tissues and cells. The levels of sCD58 (a soluble form of CD58) in the cell supernatants and serum were assessed by ELISA. CCK-8, colony formation, and xenograft assays were used to detect the function of CD58 on proliferation in vitro and in vivo. Transwell assay and sphere formation assay were performed to evaluate the effect of CD58 and sCD58 on metastasis and self-renewal ability of HCC cells. Western blotting, immunofluorescence (IF), TOP/FOP Flash reporter assay, and subcellular fractionation assay were conducted to investigate the molecular regulation between CD58/sCD58 and AKT/GSK-3β/β-catenin axis in HCC cells.ResultsCD58 was significantly upregulated in HCC tissues. Elevation of CD58 expression correlated with more satellite foci and vascular invasion, and poorer tumor-free and overall survival in HCC patients. Higher sCD58 levels were in HCC patients' serum compared to healthy individuals. Functionally, CD58 promotes the proliferation of HCC cells in vitro and in vivo. Meanwhile, CD58 and sCD58 induce metastasis, self-renewal and pluripotency in HCC cells in vitro. Mechanistically, CD58 activates the AKT/GSK-3β/β-catenin signaling pathway by increasing phosphorylation of AKT or GSK3β signaling, promoting expression of Wnt/β-catenin target proteins and TCF/LEF-mediated transcriptional activity. Furthermore, AKT activator SC-79 or inhibitor LY294002 abolished the inhibitory effect of CD58 silencing on the proliferation, metastasis, and stemness of HCC cells.ConclusionsTaken together, CD58 promotes HCC progression and metastasis via activating the AKT/GSK-3β/β-catenin pathway, suggesting that CD58 is a novel prognostic biomarker and therapeutic target for HCC.

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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.

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