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.

MicroRNA‐193b‐3p regulates matrix metalloproteinase 19 expression in interleukin‐1β‐induced human chondrocytes

“…The functions of most miRNAs, however, remain undefined. Current reports experimentally verified that at least four transcription factors (ETS1, MAX, NF‐κB, RELB) were directly regulated by miR‐193b‐3p, while CCL2 production was regulated indirectly . For the latter, Ets‐1 may be involved in the iNOS gene transcription through interaction with NF‐κB, and may repress COL2A1 gene transcription by interacting with at least two sites in the COL2A1 promoter .…”

C/EBPδ demonstrates a dichotomous role in tumor initiation and promotion of epithelial carcinoma

“…Although the connection between C/EBPδ and miRNA requires further study, several publications have highlighted the role of C/EBPδ in regulating miRNA resulting in downstream phenotypical differences in cells with and without C/EBPδ, as is the case of miR-193b in urothelial human carcinoma's which demonstrated and anti-tumorigenic function of C/EBPδ through miR-193b in NUTB1 human urothelial carcinoma cell line (Lin, Yeh et al 2017). In this context, we suggest a model whereby C/EBPδ's initial expression in premalignant FTE would slow cell cycle progression and allow these cells to acquire epithelial phenotype with potential to avoid anoikis and migrate to the ovary.…”

Knockdown of linc00152 inhibits the progression of gastric cancer by regulating microRNA-193b-3p/ETS1 axis

“…Also, ETS1 as a target of miR-193b has been reported in hepatocellular cancer and urothelial cancer cells. 38,39 ETS1, a member of ETS family, can functionally and physically interact with many proteins including transcriptional factors, kinases and acetyl transferases. 40 Also, the dysregulation of ETS1 plays vital roles in numerous biological processes such as haematopoietic development, angiogenesis and apoptosis.…”