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

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

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • CCAAT-Enhancer-Binding Protein-delta / genetics*
  • Carcinoma, Transitional Cell / drug therapy
  • Carcinoma, Transitional Cell / genetics*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Movement
  • Cisplatin / pharmacology
  • Cyclin D1 / genetics*
  • Down-Regulation
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MicroRNAs / genetics*
  • Proto-Oncogene Protein c-ets-1 / genetics*
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics*

Substances

  • 3' Untranslated Regions
  • CCND1 protein, human
  • CEBPD protein, human
  • ETS1 protein, human
  • MIRN193 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Protein c-ets-1
  • Cyclin D1
  • CCAAT-Enhancer-Binding Protein-delta
  • Cisplatin