| Popis: |
MicroRNAs are a class of small non-coding RNAs which modulate a wide range of physiological and pathological processes by negatively regulating gene expression at the post-transcriptional level. MicroRNAs have been found to be important modulators of the tumorigenesis and metastasis formation of different human cancers, including breast cancer. Here we prove that miR-515-5p belongs to a particular subset of microRNAs which mediate estradiol (E2) action in the carcinogenesis of estrogen receptor-positive breast cancers, in which proliferation is highly dependent on E2. We show that miR-515-5p downregulation is the main responsible for the positive effect of E2 in the expression of SK1, an oncogenic enzyme required for E2-dependent breast cancer tumorigenesis. Upon E2 stimulation, estrogen receptor α (ERα) directly represses the transcription of miR-515-5p which leads to the upregulation of SK1 expression as a result of its reduced availability to target SK1. By conducting the first functional studies of miR-515-5p, here we also demonstrate that miR-515-5p plays a tumour suppressive role in breast cancer. miR-515-5p was found to inhibit breast cancer proliferation by inducing caspase-dependent apoptosis via SK1 and to repress breast cancer cell motility mainly by targeting MARK4, an enzyme implicated in the regulation of cell cytoskeleton dynamics. Overall, we identify a new signaling pathway involving ERα, SK1 and miR-515-5p and a new role for miR-515-5p which highlights its therapeutic potential for the treatment of breast cancer. |
