title: Interleukin-20 promotes migration of bladder cancer cells through extracellular signal-regulated kinase (ERK)-mediated MMP-9 protein expression leading to nuclear factor (NF-κB) activation by inducing the up-regulation of p21(WAF1) protein expression.
abstract: The role of inflammatory cytokine interleukin-20 (IL-20) has not yet been studied in cancer biology. Here, we demonstrated up-regulation of both IL-20 and IL-20R1 in muscle-invasive bladder cancer patients. The expressions of IL-20 and IL-20R1 were observed in bladder cancer 5637 and T-24 cells. We found that IL-20 significantly increased the expression of matrix metalloproteinase (MMP)-9 via binding activity of NF-κB and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2, JNK, p38 MAPK, and JAK-STAT signaling. Among the pathways examined, only ERK1/2 inhibitor U0126 significantly inhibited IL-20-induced migration and invasion. Moreover, siRNA knockdown of IL-20R1 suppressed migration, invasion, ERK1/2 activation, and NF-κB-mediated MMP-9 expression induced by IL-20. Unexpectedly, the cell cycle inhibitor p21(WAF1) was induced by IL-20 treatment without altering cell cycle progression. Blockade of p21(WAF1) function by siRNA reversed migration, invasion, activation of ERK signaling, MMP-9 expression, and activation of NF-κB in IL-20-treated cells. In addition, IL-20 induced the activation of IκB kinase, the degradation and phosphorylation of IκBα, and NF-κB p65 nuclear translocation, which was regulated by ERK1/2. IL-20 stimulated the recruitment of p65 to the MMP-9 promoter region. Finally, the IL-20-induced migration and invasion of cells was confirmed by IL-20 gene transfection and by addition of anti-IL-20 antibody. This is the first report that p21(WAF1) is involved in ERK1/2-mediated MMP-9 expression via increased binding activity of NF-κB, which resulted in the induction of migration in IL-20/IL-20R1 dyad-induced bladder cancer cells. These unexpected results might provide a critical new target for the treatment of bladder cancer.
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: Seok-Cheol
authors.initials: SC
authors.lastname: Cho
authors.forename: Eo-Jin
authors.initials: EJ
authors.lastname: Lee
authors.forename: Sangtae
authors.initials: S
authors.lastname: Kim
authors.forename: Soo-Bok
authors.initials: SB
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: D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D007378:Interleukins; D016328:NF-kappa B; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; C422042:interleukin 20