Microrna-182 Targets Smad7 To Potentiate Tgf Beta-Induced Epithelial-Mesenchymal Transition And Metastasis Of Cancer Cells

The transforming growth factor beta (TGF beta) pathway plays critical roles during cancer cell epithelial-mesenchymal transition (EMT) and metastasis. SMAD7 is both a transcriptional target and a negative regulator of TGF beta signalling, thus mediating a negative feedback loop that may potentially restrain TGF beta responses of cancer cells. Here, however, we show that TGFb treatment induces SMAD7 transcription but not its protein level in a panel of cancer cells. Mechanistic studies reveal that TGFb activates the expression of microRNA-182 (miR-182), which suppresses SMAD7 protein. miR-182 silencing leads to SMAD7 upregulation on TGF beta treatment and prevents TGF beta-induced EMT and invasion of cancer cells. Overexpression of miR-182 promotes breast tumour invasion and TGFb-induced osteoclastogenesis for bone metastasis. Furthermore, miR-182 expression inversely correlates with SMAD7 protein in human tumour samples. Therefore, our data reveal the miR-182-mediated disruption of TGF beta self-restraint and provide a mechanism to explain the unleashed TGF beta responses in metastatic cancer cells.