Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs which can serve as oncogenes or tumor suppressor genes in human cancers. Herein, the transcriptomic differences of miRNAs in ccRCC were globally assessed using publicly available microarray dataset (GSE71302) from Gene Expression Omnibus (GEO) and we identified miR-138 as a potential onco-suppressive miRNA. We further found that the expression of miR-138 was dramatically decreased in ccRCC cell lines and clinical ccRCC tissue samples, and the low miR-138 expression was closely correlated with tumor progression and prognosis in ccRCC patients. Overexpression of miR-138 inhibited, whereas downregulation of miR-138 promoted, the proliferation, migration and invasion of ccRCC cells in vitro, suggesting that miR-138 may function as a tumor suppressor in ccRCC. Furthermore, for the first time, we identified the EMT-related transcription factor SOX4 as a direct target gene of miR-138, evidenced by the direct binding of miR-138 with the 3'UTR of SOX4. Notably, the EMT marker E-cadherin or vimentin was also upregulated or downregulated upon miR-138 overexpression, and these effects were restored by SOX4 overexpression. We have also shown SOX4 overexpression reversed the attenuated migratory and invasive capacities mediated by miR-138. These results revealed that miR-138 functions as a tumor suppressor in ccRCC by targeting SOX4 and the EMT process and might represent a potential target in the treatment of human ccRCC.