MiR-200c Targets CDK2 and Suppresses Tumorigenesis in Renal Cell Carcinoma

Unlabelled: miRNA expression profiles are widely investigated in the major cancers, but their specific roles and functions in cancers have not yet to be fully elucidated. In this study, miRNA expression profiles were determined in clear cell renal cell carcinomas (ccRCC) and in matched normal kidney tissues by using a miRNA microarray platform which covers a total of 851 human miRNAs. Differential expression of 74 miRNAs were identified between ccRCC specimens and their matched adjacent noncancerous tissues, of which 30 were significantly upregulated in ccRCCs, and the other 44 were downregulated (fold change ≥ 2, P < 0.05). Interestingly, miR-200c was commonly downregulated in ccRCC specimens and ccRCC cell lines with significant functional consequences. Growth curve and FACS assay indicated that overexpression of miR-200c suppressed cell growth and induced cell-cycle arrest at G0-G1 phases in SN12-PM6 and 786-O cells. Furthermore, miR-200c could suppress in vivo tumor growth of SN12-PM6 cells in mice. Bioinformatics exposed cyclin-dependent kinase 2 (CDK2) as a potential target of miR-200c, which was validated using a luciferase reporter assay. Mechanistic investigations revealed that miR-200c was directly responsible for suppressing the expression of CDK2 in ccRCC cell lines and xenografts. Taken together, miR-200c plays an antioncogenic role in ccRCC, through controlling cell growth and cell-cycle progression by downregulating the G1-S regulator CDK2.

Implications: miR-200c exerts its novel antioncogenic function in renal cell carcinoma by controlling CDK2-dependent cell growth and cell-cycle progression.