MicroRNA expression signatures of stage, grade, and progression in clear cell RCC

Clear cell RCC is the most common, and more likely to metastasize, of the three main histological types of RCC. Pathologic stage is the most important prognostic indicator and nuclear grade can predict outcome within stages of localized RCC. Epithelial tumors are thought to accumulate a series of genetic and epigenetic changes as they progress through well-defined clinical and histopathological changes. MicroRNAs (miRNAs) are involved in the regulation of mRNA expression from many human genes and miRNA expression is dysregulated in cancer. To better understand the contribution of dysregulated miRNA expression to the progression and biology of ccRCC, we examined the differences in expression levels of 723 human miRNAs through a series of analyses by stage, grade, and disease progression status in a large series of 94 ccRCC. We found a consistent signature that included significant upregulation of miR-21-5p, 142-3p, let-7g-5p, let-7i-5p and 424-5p, as well as downregulation of miR-204-5p, to be associated with ccRCC of high stage, or high grade, or progression. Discrete signatures associated with each of stage, grade, or progression were also identified. The let-7 family was significantly downregulated in ccRCC compared with normal renal parenchyma. Expression of the 6 most significantly differentially expressed miRNAs between ccRCC was verified by stem-loop qRT-PCR. Pathways predicted as targets of the most significantly dysregulated miRNAs included signaling, epithelial cancers, metabolism, and epithelial to mesenchymal transition. Our studies help to further elucidate the biology underlying the progression of ccRCC and identify miRNAs for potential translational application.