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J Cell Biochem. 2017 Jun;118(6):1563-1573. doi: 10.1002/jcb.25818. Epub 2016 Dec 20.

MiR-193b Mediates CEBPD-Induced Cisplatin Sensitization Through Targeting ETS1 and Cyclin D1 in Human Urothelial Carcinoma Cells.

Lin SR1, Yeh HC2,3,4, Wang WJ5, Ke HL3,4, Lin HH3, Hsu WC1,3,6, Chao SY7, Hour TC1,6, Wu WJ2,3,4,8, Pu YS9, Huang AM1,6,10,11.

Author information

1
Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
2
Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
3
Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
4
Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
5
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
6
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
7
Department of Computer Science and Information Engineering, Chien Hsin University of Science and Technology, Taoyuan, Taiwan.
8
Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
9
Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan.
10
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
11
Ph. D. Program in Toxicology, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.

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.

KEYWORDS:

CELL CYCLE; CHEMOTHERAPEUTIC DRUGS; MIGRATION; MicroRNA-193b-3p; TRANSCRIPTION FACTOR; UROTHELIAL CARCINOMA

PMID:
27918099
DOI:
10.1002/jcb.25818
[Indexed for MEDLINE]

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