miRNA-133b and miRNA-135a induce apoptosis via the JAK2/STAT3 signaling pathway in human renal carcinoma cells

Aberrantly expressed microRNAs (miRNAs) are involved in many diseases including cancer. In clear cell renal cell carcinoma (ccRCCs) expression of miR-133b and miR-135a is reduced compared to control tissue and other sarcomas but the functional effects of this downregulation are not fully understood. This study aimed at evaluating the miR-133b and miR-135a expression profiles in different RCC subtypes and the functional role of these miRNAs. Viability and apoptosis were examined in three different ccRCC cell lines (786-O, A498 and SN12-PM6) after over-expression of these miRNAs. The modulation of JAK2 and the JAK2/STAT3 pathways was determined by Western blot. Transient transfection of miR-133b and miR-135a reduced viability and induced apoptosis by inhibition of JAK2 expression and its phosphorylation and activation of caspase 3 and 7 in all three ccRCC cell lines. p-STAT3 and Bcl-2 expression was reduced after miRNA transfection whereas only slight influence on Bcl-2 L11 (BIM) was detected. Our results demonstrate that miR-133b and miR-135a which are down-regulated in wildtype and mutated ccRCCs, induce apoptosis in vitro by a signaling cascade involving JAK2, STAT3 and Bcl-2. Therefore, overexpression of these miRNAs seems to functionally counteract oncogenic signalling pathways in ccRCCs. (C) 2016 Published by Elsevier Masson SAS.