MicroRNA-182 targets SMAD7 to potentiate TGF?-induced epithelial-mesenchymal transition and metastasis of cancer cells.

ABSTRACT: The transforming growth factor ? (TGF?) 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? signalling, thus mediating a negative feedback loop that may potentially restrain TGF? responses of cancer cells. Here, however, we show that TGF? treatment induces SMAD7 transcription but not its protein level in a panel of cancer cells. Mechanistic studies reveal that TGF? activates the expression of microRNA-182 (miR-182), which suppresses SMAD7 protein. miR-182 silencing leads to SMAD7 upregulation on TGF? treatment and prevents TGF?-induced EMT and invasion of cancer cells. Overexpression of miR-182 promotes breast tumour invasion and TGF?-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? self-restraint and provide a mechanism to explain the unleashed TGF? responses in metastatic cancer cells.

SUBMITTER: Yu J 

PROVIDER: S-EPMC5187443 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature