MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells.
Jingyi YuRong LeiXueqian ZhuangXiaoxun LiGang LiSima LevMiguel F SeguraXue ZhangGuohong HuPublished in: Nature communications (2016)
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.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- cell proliferation
- signaling pathway
- long non coding rna
- poor prognosis
- high glucose
- endothelial cells
- squamous cell carcinoma
- genome wide
- diabetic rats
- inflammatory response
- binding protein
- big data
- heat shock protein
- protein protein
- artificial intelligence
- machine learning
- data analysis
- small molecule
- deep learning
- induced pluripotent stem cells