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

Jingyi Yu, Rong Lei, Xueqian Zhuang, Xiaoxun Li, Gang Li, Sima Lev, Miguel F. Segura, Xue Zhang and Guohong Hu ()
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Jingyi Yu: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences
Rong Lei: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences
Xueqian Zhuang: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences
Xiaoxun Li: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences
Gang Li: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences
Sima Lev: Weizmann Institute of Science
Miguel F. Segura: New York University School of Medicine
Xue Zhang: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences
Guohong Hu: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13884

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