title: Interleukin-28A triggers wound healing migration of bladder cancer cells via NF-κB-mediated MMP-9 expression inducing the MAPK pathway.
abstract: Interleukin (IL)-28A, also called IFN-λ2, is a member of the classIIcytokine family and has demonstrated anti-proliferative and anti-viral signals. The present study demonstrated migration inducement of IL-28A-treated bladder cancer cells - a novel function. RNA microarray analysis showed an enhanced expression of IL-28A and its receptor IL-28AR1 in muscle invasive urothelial carcinoma in a human bladder. Strong expression of IL-28A and IL-28AR1 was detected in bladder cancer tissues and cell lines (5637, T-24, and HT1376 cells), as determined by real-time PCR and immunoblot analysis. IL-28A treatment induced migration of bladder cancer cells, independent of the cell growth. IL-28AR1-specific small interfering RNA (si-IL-28AR1) inhibited the induction of migration in IL-28A-treated cells. IL-28A treatment stimulated the expression of matrix metalloproteinases-9 (MMP-9) via activation of transcription factor NF-κB. Gene knockdown for MMP-9 and the p65 subunit of NF-κB, using siRNA transfection, suppressed wound healing migration in IL-28A-treated bladder cancer cells. Also, treatment with IL-28A induced activation of mitogen-activated protein kinase (MAPK) in bladder cancer cells. MAPK function blockage by a MAPK-specific inhibitor showed that MAPK phosphorylation is required for IL-28A-induced MMP-9 expression through activation of NF-κB. The transient transfection of bladder cancer cells with ERK1/2 knock down (si-ERK1/2) and dominant negative p38 (DNp38) suppressed IL-28A-induced migration. IL-28A-induced induction of MMP-9 expression, MAPK activation, and DNA binding activity of NF-κB was abolished in the presence of IL-28A neutralizing antibody or by transfection of si-IL-28AR1. These results show that IL-28A/IL-28AR1 dyad-induced wound healing migration requires NF-κB-mediated MMP-9 expression by MAPK activation.
authors.affiliation: Department of Biotechnology, Chungju National University, Chungju, Chungbuk 380-702, South Korea.
authors.forename: Se-Jung
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jung-Hyurk
authors.initials: JH
authors.lastname: Lim
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: D002465:Cell Movement; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing; D000095022:Interferon Lambda
chemical_list: D007378:Interleukins; D020780:Matrix Metalloproteinase 9; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; C000624353:interferon-lambda, human; D000095022:Interferon Lambda