Urinary microRNAs as potential biomarkers for differentiating the "atypical urothelial cells" category of the Paris system for reporting urine cytology

MicroRNA is known to be an important regulator of gene expression. The microRNAs that were found to be differentially expressed in normal urothelium and urothelial carcinomas in the literature were selected and meaningful microRNAs were validated using urothelial tumor cells lines; formalin-fixed and paraffin-embedded (FFPE) tissues; and urine samples for both the definitely benign and malignant categories. Diagnostic utility was also assessed by applying validated microRNAs to urine specimens in the "atypical urothelial cells" category of the Paris System for Reporting Urine Cytology. Among the 25 consistently directed microRNAs in 2 or more studies, 14 microRNAs were upregulated and 11 downregulated. In urothelial tumor cell lines, 3 microRNAs were upregulated and 8 microRNAs were downregulated. In the step using FFPE tissues, four microRNAs (miR-145, miR-133a, miR-125b, and miR-99a) levels were downregulated and four microRNAs (miR-96, miR-141, miR-200c, and miR-205) were upregulated in the entire spectrum of urothelial neoplasms. Similar expression profiles were observed in urine specimens of "negative for high-grade urothelial carcinoma" and "urothelial carcinoma". The expression of miR-99a revealed different trends among the atypical urothelial categories. The findings from this study show that consistently upregulated or downregulated microRNAs might be involved in tumorigenesis or progression of urothelial carcinoma and that they could be used as potential diagnostic or prognostic markers.