title: MiR-193b Mediates CEBPD-Induced Cisplatin Sensitization Through Targeting ETS1 and Cyclin D1 in Human Urothelial Carcinoma Cells.
abstract: Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) plays multiple roles in tumor progression. Studies have demonstrated that cisplatin (CDDP) induced CEBPD expression and had led to chemotherapeutic drug resistance. However, the underlying molecular mechanisms of CDDP-regulated CEBPD expression and its relevant roles in CDDP responses remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression in a sequence-specific manner. Abnormal miRNAs expression is associated with tumor progression. In current study, a large-scale PCR-based miRNA screening was performed to identify CEBPD-associated miRNAs in urothelial carcinoma cell line NTUB1. Eleven miRNAs were selected with more than twofold changes. MiR-193b-3p, a known tumor suppressor, down-regulated proto-oncogenes Cyclin D1, and ETS1 expression and led to cell cycle arrest, cell invasion, and migration inhibition. The expression of miR-193b-3p was associated with the DNA binding ability of CEBPD in CDDP response. CEBPD knocking-down approach provided a strong evidence of the positive correlation between CEBPD and miR-193b-3p. CDDP-induced CEBPD trans-activated miR-193b-3p expression and it directly targeted the 3'-UTR of Cyclin D1 and ETS1 mRNA, and silenced the protein expression. In addition, miR-193b-3p also inhibited cell migration activity, arrested cell at G1 phase, and sensitized NTUB1 to CDDP treatment. In conclusion, this study indicates that CEBPD exhibits an anti-tumorigenic function through transcriptionally activating miR-193b-3p expression upon CDDP treatment. This study provides a new direction for managing human urothelial carcinoma. J. Cell. Biochem. 118: 1563-1573, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Siao-Ren
authors.initials: SR
authors.lastname: Lin
authors.affiliation: Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hsin-Chih
authors.initials: HC
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hung-Lung
authors.initials: HL
authors.lastname: Ke
authors.affiliation: Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wei-Chi
authors.initials: WC
authors.lastname: Hsu
authors.affiliation: Department of Computer Science and Information Engineering, Chien Hsin University of Science and Technology, Taoyuan, Taiwan.
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Chao
authors.affiliation: Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tzyh-Chyuan
authors.initials: TC
authors.lastname: Hour
authors.affiliation: Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.|Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Jeng
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.affiliation: Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Ph. D. Program in Toxicology, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: A-Mei
authors.initials: AM
authors.lastname: Huang
mesh_terms: D020413:3' Untranslated Regions; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D002945:Cisplatin / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C530104:CCND1 protein, human; C497252:CEBPD protein, human; C494041:ETS1 protein, human; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D050784:Proto-Oncogene Protein c-ets-1; D019938:Cyclin D1; D051743:CCAAT-Enhancer-Binding Protein-delta; D002945:Cisplatin
keywords: CELL CYCLE; CHEMOTHERAPEUTIC DRUGS; MIGRATION; MicroRNA-193b-3p; TRANSCRIPTION FACTOR; UROTHELIAL CARCINOMA