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, Shanghai 200031, China.
Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
Nat Commun. 2016 Dec 20;7:13884. doi: 10.1038/ncomms13884.
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.
转化生长因子β（TGFβ）途径在癌细胞上皮-间充质转化（EMT）和转移过程中发挥关键作用。SMAD7 既是 TGFβ 信号的转录靶标，也是其负调控因子，从而介导负反馈回路，可能限制癌细胞对 TGFβ 的反应。然而，在这里，我们表明 TGFβ 在一系列癌细胞中诱导 SMAD7 转录，但不诱导其蛋白水平。机制研究表明，TGFβ 激活 microRNA-182（miR-182）的表达，后者抑制 SMAD7 蛋白。miR-182 沉默导致 TGFβ 处理时 SMAD7 上调，并防止 TGFβ 诱导的 EMT 和癌细胞侵袭。miR-182 的过表达促进乳腺癌肿瘤侵袭和 TGFβ 诱导的破骨细胞生成以促进骨转移。此外，miR-182 的表达与人类肿瘤样本中的 SMAD7 蛋白呈负相关。因此，我们的数据揭示了 miR-182 介导的 TGFβ 自我约束的破坏，并提供了一种机制来解释转移性癌细胞中不受控制的 TGFβ 反应。
