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

Jingyi Yu,R. Lei,Xueqian Zhuang,Xiaoxun Li,Gang Li,S. Lev,M. Segura,Xue Zhang,G. Hu

Published 2016 in Nature Communications

ABSTRACT

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

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