Role of pre- ( and ) in regulation of gene expression and molecular pathogenesis in renal cell carcinoma.

Analyses of our previously determined microRNA (miRNA) expression signature of renal cell carcinoma (RCC) and The Cancer Genome Atlas (TCGA) database revealed that both strands of the pre- (the guide strand) and (the passenger strand)- are closely associated with poor prognosis of RCC patients ( = 0.0411 and = 0.022, respectively). In this study we investigated the functional significance of these miRNAs and identified gene targets involved in RCC pathogenesis. Ectopic expression of these miRNAs significantly attenuated the malignant phenotypes including proliferation, migration and invasion of two RCC cell lines, 786-O and A498. A combination of genome-wide gene expression and database analyses revealed 36 and 34 genes as putative target oncogenes regulated by and , respectively, in RCC cells. Among these targets, expression of aquaporin9 (), a water channel protein, was directly regulated by both and , and high expression levels of were significantly associated with poor prognosis of RCC patients ( = 2.03e-05). Multivariate analysis indicated that expression is an independent prognostic factor for RCC patients. Aberrant AQP9 expression at both the gene and protein level was detected in RCC clinical specimens. siRNA-mediated knockdown of by si- inhibited the malignant phenotypes of RCC cells. Rescue assays of overexpression showed that the axis was closely involved in RCC oncogenesis. The identification of antitumor miRNAs and their targets will contribute to an increased understanding of the molecular pathogenesis of RCC.