title: Interleukin-5 enhances the migration and invasion of bladder cancer cells via ERK1/2-mediated MMP-9/NF-κB/AP-1 pathway: involvement of the p21WAF1 expression.
abstract: Inflammatory cytokines may be a critical component of epithelial cancer progression. We examined the role of interleukin (IL)-5 in the migration of bladder cancer cells. The expression of IL-5 and its receptor IL-5Rα was enhanced in patients with muscle invasive bladder cancers (MIBC), and then it was detected in bladder cancer cell lines 5637 and T-24. IL-5 increased migration and MMP-9 expression via activation of transcription factors NF-κB and AP-1, and induced activation of ERK1/2 and Jak-Stat signaling in both cells. Treatment with ERK1/2 inhibitor U0126 significantly inhibited induction of migration, MMP-9 expression, and activation of NF-κB and AP-1 in IL-5-treated cells. However, none of the Jak inhibitors affected the IL-5-induced migration of bladder cancer cells. Moreover, gene knockdown for IL-5Rα, using siRNA transfection, suppressed migration, ERK1/2 activation, MMP-9 expression, as well as the binding activation of NF-κB and AP-1 in IL-5-treated bladder cancer cells. Similar results were observed in βc siRNA (si-βc) transfected cells. Unexpectedly, IL-5 treatment resulted in significant induction of p21WAF1 in both cell lines. The p21WAF1-specific small interfering RNA inhibited IL-5-induced cell migration, ERK activity, MMP-9 expression, and activation of NF-κB and AP-1 in bladder cancer cells. The effects of IL-5-induced cell responses were confirmed by transfection of IL-5 gene, which demonstrated that p21WAF1 participates in the induction of cell migration, leading to an increase in ERK1/2-mediated MMP-9 expression through activation of NF-κB and AP-1 in IL-5-treated bladder cancer cells. These unexpected results provide a theoretical basis for the therapeutic targeting of IL-5 in bladder cancer.
authors.affiliation: Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, South Korea.
authors.forename: Eo-Jin
authors.initials: EJ
authors.lastname: Lee
authors.forename: Se-Jung
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sangtae
authors.initials: S
authors.lastname: Kim
authors.forename: Seok-Cheol
authors.initials: SC
authors.lastname: Cho
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015848:Interleukin-5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019042:Muscle Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015848:Interleukin-5; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D020780:Matrix Metalloproteinase 9
keywords: ERK1/2; IL-5; IL-5Rα; MMP-9; Migration; p21WAF1