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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

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

Yu Jingyi J Lei Rong R Zhuang Xueqian X Li Xiaoxun X Li Gang G Lev Sima S Segura Miguel F MF Zhang Xue X Hu Guohong G

Nature communications 20161220

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 activate ...[more]

PMID: 27996004

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Project description:Background: Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of non-small cell lung cancer (NSCLC). However, the mechanisms through which miR-182-5p regulate NSCLC progression have not been established. This study aimed at evaluating the expression levels of miR-182-5p in human NSCLC and its function in lung cancer cells. Endothelial PAS Domain-containing protein 1 (EPAS1; also referred to as hypoxia-inducing factor 2A, HIF-2α) is a transcription factor that is responsible for induction of genes related to cell survival under hypoxia conditions. Hypoxia, an inherent feature of solid tumors, is associated with aggressive phenotypes, as well as resistance to radiotherapy and chemotherapy, which predict metastasis and poor prognosis. Methods: The Cancer Genome Atlas (TCGA) dataset was used to investigate the association between miR-182-5p expression and clinicopathological characteristics as well as prognosis of NSCLC patients. Target genes of miR-182-5p were identified using the PITA, miRmap, microT, miRanda, PicTar, and TargetScan prediction tools. Transwell assays were performed to determine the potential functions of miR-182-5p in lung cancer cells. Luciferase reporter assays were performed to analyze regulation of the putative target of miR-182-5p while western blot assays were used to validate the luciferase results. Results: miR-182-5p was found to be upregulated in NSCLC tissues and acted as an independent prognostic factor for tumor recurrence in NSCLC patients. Functionally, overexpression of miR-182-5p promoted lung cancer cell migration and invasion. Genome-wide gene expression analysis and luciferase report assays revealed that EPAS1 is a direct target of miR-182-5p. EPAS1 was negatively correlated with miR-182-5p expression in NSCLC tissues. Univariate and multivariate survival analyses identified EPAS1 as an independent prognostic factor for overall survival (OS) in NSCLC. Conclusions: These findings imply that miR-182-5p promotes NSCLC progression by targeting EPAS1 and is, therefore, a potential indicator of tumor recurrence in NSCLC patients.

Dataset Information

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

Publications

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

Similar Datasets

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