Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2013, PMID: 23271730

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.

Lee, Se-Jung; Cho, Seok-Cheol; Lee, Eo-Jin; Kim, Sangtae; Lee, Soo-Bok; Lim, Jung-Hyurk; Choi, Yung Hyun; Kim, Wun-Jae; Moon, Sung-Kwon

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.

Diseases/Pathways annotated by Medline MESH: Neoplasm Invasiveness, Urinary Bladder Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

JAK-STAT → IL-20: " We found that IL-20 significantly increased the expression of matrix metalloproteinase (MMP)-9 via binding activity of NF-?B and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2, JNK, p38 MAPK, and JAK-STAT signaling "

MAPK → IL-20: " We found that IL-20 significantly increased the expression of matrix metalloproteinase (MMP)-9 via binding activity of NF-?B and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2, JNK, p38 MAPK , and JAK-STAT signaling "

ERK1/2 → IL-20: " We found that IL-20 significantly increased the expression of matrix metalloproteinase (MMP)-9 via binding activity of NF-?B and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2 , JNK, p38 MAPK, and JAK-STAT signaling "

JAK-STAT → IL-20: " We found that IL-20 significantly increased the expression of matrix metalloproteinase (MMP)-9 via binding activity of NF-?B and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2, JNK, p38 MAPK, and JAK-STAT signaling "

matrix metalloproteinase (MMP)-9 → IL-20: " We found that IL-20 significantly increased the expression of matrix metalloproteinase (MMP)-9 via binding activity of NF-?B and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2, JNK, p38 MAPK, and JAK-STAT signaling "

ERK1/2 → IL-20: " Moreover, siRNA knockdown of IL-20R1 suppressed migration, invasion, ERK1/2 activation, and NF-?B mediated MMP-9 expression induced by IL-20 "

ERK1/2 → IL-20: " Moreover, siRNA knockdown of IL-20R1 suppressed migration, invasion, ERK1/2 activation, and NF-?B mediated MMP-9 expression induced by IL-20 "

MMP-9 → IL-20: " Moreover, siRNA knockdown of IL-20R1 suppressed migration, invasion, ERK1/2 activation, and NF-?B mediated MMP-9 expression induced by IL-20 "

p21 → IL-20: " Unexpectedly, the cell cycle inhibitor p21 ( WAF1 ) was induced by IL-20 treatment without altering cell cycle progression "

MMP-9 → ERK: " Blockade of p21 ( WAF1 ) function by siRNA reversed migration, invasion, activation of ERK signaling, MMP-9 expression, and activation of NF-?B in IL-20 treated cells "

p65 → IL-20: " In addition, IL-20 induced the activation of I?B kinase, the degradation and phosphorylation of I?Ba, and NF-?B p65 nuclear translocation, which was regulated by ERK1/2 "

NF-?B p65 → IL-20: " In addition, IL-20 induced the activation of I?B kinase, the degradation and phosphorylation of I?Ba, and NF-?B p65 nuclear translocation, which was regulated by ERK1/2 "

MMP-9 → p21: " This is the first report that p21 ( WAF1 ) is involved in ERK1/2 mediated MMP-9 expression via increased binding activity of NF-?B, which resulted in the induction of migration in IL-20/IL-20R1 dyad induced bladder cancer cells "

MMP-9 → ERK1/2: " This is the first report that p21 ( WAF1 ) is involved in ERK1/2 mediated MMP-9 expression via increased binding activity of NF-?B, which resulted in the induction of migration in IL-20/IL-20R1 dyad induced bladder cancer cells "

Manually curated Databases

No curated data.