title: EPO gene expression induces the proliferation, migration and invasion of bladder cancer cells through the p21WAF1‑mediated ERK1/2/NF-κB/MMP-9 pathway.
abstract: Erythropoietin (EPO) is a cytokine that modulates the production of red blood cells. Previous studies have contradicted the assumed role of EPO in tumor cell proliferation. In the present study, we investigated the effect of EPO in the proliferation, migration and invasion that is involved in the signaling pathways and cell-cycle regulation of bladder cancer 5637 cells. The results showed that an overexpression of the EPO gene has a potent stimulatory effect on DNA synthesis, migration and invasion. EPO gene expression increased the expression of matrix metalloproteinase (MMP)-9 via the binding activity of NF-κB, AP-1 and Sp-1 in 5637 cells. The transfection of 5637 cells with the EPO gene induced the phosphorylation of ERK1/2. Treatment with ERK1/2 inhibitor U0126 significantly inhibited the increased proliferation, migration and invasion of EPO gene-transfected cells. U0126 treatment suppressed the induction of MMP-9 expression through NF-κB binding activity in EPO gene transfectants. In addition, EPO gene expression was correlated with the upregulation of cyclins/CDKs and the upregulation of the CDK inhibitor p21WAF1 expression. Finally, the inhibition of p21WAF1 function by siRNA blocked the proliferation, migration, invasion and phosphorylation of ERK1/2 signaling, as well as MMP-9 expression and activation of NF-κB in EPO gene-transfected cells. These novel findings suggest that the molecular mechanisms of EPO contribute to the progression and development of bladder tumors.
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Anseong, Gyeonggi 456‑756, Republic of Korea.
authors.forename: Sung Lyea
authors.initials: SL
authors.lastname: Park
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Anseong, Gyeonggi 456‑756, Republic of Korea.
authors.forename: Se Yeon
authors.initials: SY
authors.lastname: Won
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Anseong, Gyeonggi 456‑756, Republic of Korea.
authors.forename: Jun-Hui
authors.initials: JH
authors.lastname: Song
authors.affiliation: Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Anseong, Gyeonggi 456‑756, Republic of Korea.
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D002070:Butadienes; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C554270:EPO protein, human; D009570:Nitriles; C113580:U 0126; D004921:Erythropoietin