ADP‐ribosylation factor 6 (ARF6) is a well‐studied protein that is involved in multiple biological functions including cell migration and invasion. The mechanism by which ARF6 regulates the migration and invasion of upper tract urothelial carcinoma (UTUC) is still unknown. MiR‐145‐5p is a tumor suppressor microRNA, which is downregulated in several cancer types. We aimed to elucidate the molecular mechanism underlying the regulation of ARF6 by miR‐145‐5p in UTUC. ARF6 expression was observed to be higher in UTUC tissues than paired adjacent normal tissues. A reverse correlation between ARF6 and miR‐145‐5p was found in UTUC tissues. MiR‐145‐5p inhibited ARF6 expression by directly targeting its 3′‐UTR. The functional studies indicated that ARF6 expression reversed the miR‐145‐5p‐reduced tumor cell migration and invasion. Notably, miR‐145‐5p reduced MMP2, N‐cadherin, FAK and MMP7, and elevated E‐cadherin protein levels in vitro; however, the above effects were reversed by ARF6. Further, the expression of epithelial‐to‐mesenchymal transition (EMT) markers and cell invasion was suppressed by knocking down MMP7 in UTUC cells. These findings suggest that miR‐145‐5p may suppress UTUC cell motility and invasion by targeting ARF6/MMP7 through EMT.

Background: Hypoxia has been shown to facilitate tumor progression. Hypoxia-regulated microRNA-210 (miR-210) may play an important role in carcinogenesis and tumor progression. In this study, we evaluated the clinical significance of miR-210 expression in upper tract urothelial carcinoma (UTUC).Methods: Eighty-three UTUC patients participated in this study. All of them provided cancer tissue samples and 50 of them provided non-cancerous urothelium samples. Clinicopathologic data were collected by reviewing medical records. The expression of miR-210 and hypoxia-inducible factor-1α (HIF-1α) was determined by quantitative real-time polymerase chain reaction. The relationship between clinicopathologic variables and the expression of miR-210 and HIF-1α was analyzed statistically.Results: MiR-210 is overexpressed in UTUC compared to non-cancerous urothelium (p < 0.001); it is also upregulated in high-stage and high-grade tumors (p = 0.020 and 0.049, respectively). HIF-1α is overexpressed in UTUC and correlates positively with miR-210 expression (r = 0.442, p = 0.001).Conclusion: Both miR-210 and HIF-1α are involved in promoting UTUC carcinogenesis. MiR-210 is also correlated with tumor progression. Further studies are needed to clarify the underlying mechanism.

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.

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