title: 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.
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors.forename: Huaqin
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors.forename: Peifen
authors.initials: P
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Wanshuai
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: yangsun@nju.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Electronic address: guluer@163.com.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
mesh_terms: D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D019409:Interleukin-15 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C569274:IL15 protein, human; D019409:Interleukin-15; D051176:beta Catenin; D019061:src-Family Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3