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MiR-155-5p downregulation inhibits epithelial-to-mesenchymal transition by targeting SIRT1 in human nasal epithelial cells

ABSTRACT: Epithelial-to-mesenchymal transition (EMT) in nasal epithelial cells is involved with tissue remodeling of nasal polyps. The present study investigated the molecular mechanisms through which miR-155-5p regulated EMT in chronic rhinosinusitis (CRS). Patients were divided into the following groups: CRSsNP, CRS without nasal polyposis group, CRSwNP, CRS with nasal polyposis and controls. The expression of transforming growth factor (TGF)-?1, EMT markers, sirtuin 1 (SIRT1) and miR-155-5p were determined by western blotting and reverse transcription-quantitative PCR. Cell morphology following TGF-?1 treatment in the presence of miR-155-5p inhibitors or controls was observed under a microscope. Target genes and potential binding sites between miR-155-5p and SIRT1 were predicted by TargetScan and confirmed using dual-luciferase reporter assay. In patients with CRS, the expression levels of E-cadherin were downregulated and the expression levels of TGF-?1, mesenchymal markers and miR-155-5p were upregulated. Additionally, these changes in expression levels were reduced or increased to a greater extent in the CRSwNP group compared with the CRSsNP group. Furthermore, TGF-?1 expression promoted EMT in human nasal epithelial cells (HNEpCs) and upregulated miR-155-5p expression. These effects were reversed by miR-155-5p inhibitors. Additionally, SIRT1 was predicted as a target gene of miR-155-5p. Downregulation of miR-155-5p upregulated epithelial marker expression and downregulated mesenchymal marker expression by regulating SIRT1. Therefore, the downregulation of miR-155-5p inhibited EMT in HNEpCs by targeting SIRT1.

SUBMITTER: Yang N

PROVIDER: S-EPMC7533509 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Project description:BackgroundGlioma metastasis, invasion, epithelial-mesenchymal transition (EMT) and chemoresistance indicate poor prognosis. Accumulating evidence reveals that Notch1 is an important factor in tumour progression. However, the role of Notch1 in glioma EMT and associated microRNAs (miRNAs) with the Notch pathway remain controversial.MethodsUtilizing cBioPortal database to examine the gene signature of NOTCH1 (encoding Notch1), CDH2 (encoding N-cadherin) and SNAI1 (encoding Snail-1) in disease-free survival (DFS) and overall survival (OS). We analyzed the Notch1 expression from Oncomine. We used Western blot (WB), immunohistochemistry (IHC) and immunofluorescence to determine protein levels. Transcription was evaluated by quantitative real-time (qRT)-PCR. siRNA and lentivirus were used to knock down Notch1 and overexpress miR-139-5p, respectively. The migration and invasion of glioma cells were assessed by wound healing and transwell assays. Luciferase reporter assays were utilized to verify the relationship between Notch1 and miR-139-5p. A U87-implanted intracranial model was used to study the effect of miR-139-5p on tumour growth and Notch1 suppression efficacy or EMT reversion.ResultsIt revealed the association of NOTCH1, CDH2, SNAI1 genomic alterations with decreases in DFS and OS. Notch1 was upregulated in classical and proneural subtypes of GBM, and associated with tumour grade. Notch1 inhibition suppressed the biological behaviours of metastasis, invasion and EMT. Notch1 was identified as a novel direct target of miR-139-5p. MiR-139-5p overexpression partially phenocopied Notch1 siRNA, whereas the forced expression of Notch1 reversed the effects of miR-139-5p on the invasion of glioma. Moreover, intracranial tumourigenicity and EMT behaviours were reduced by the introduction of miR-139-5p and partially mediated by the decreased Notch1 expression.ConclusionsmiR-139-5p was identified as a tumour suppressor by negatively targeting Notch1, and this work suggests a possible molecular mechanism of the miR-139/Notch1/EMT axis for glioma treatment.

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MiR-155-5p downregulation inhibits epithelial-to-mesenchymal transition by targeting SIRT1 in human nasal epithelial cells

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