MicroRNA-210-3p is transcriptionally upregulated by hypoxia induction and thus promoting EMT and chemoresistance in glioma cells

BACKGROUND: Glioma is the most common and lethal form of brain cancer. It is highly malignant and is often characterized by chemoresistance and radioresistance, which are thought to mainly result from hypoxic microenvironments. Various tumour-promoting and tumour-suppressing microRNAs (miRNAs) have been identified in gliomas; however, it is still largely unknown how miRNAs are modified by hypoxia and subsequently affect glioma. In this study, we examined the expression of miR-210-3p, a well-characterized miRNA that responds to hypoxia in glioma cell lines. METHODS: The expressions of miR-9 and miR-210-3p were analysed by using qPCR. Cell viability was measured by performing CCK-8 after eechinomycin treatment or introduction of miR-210 for 24 or 48 h. The correlation of HIF-1α expression with TGF-β were analysed using the REMBRANDT database. The biomarkers of EMT, including E-cadherin, N-cadherin and Vimentin, were detected by western blot. Apoptotic cell death was measured by performing Annexin V-FITC/PI double staining followed by flow cytometry. RESULTS: We found that miR-210-3p was induced by a mechanism dependent on the hypoxia-induced transcriptional activity of HIF-1α. Then we established a positive association between the HIF-1α and TGF-β expression levels, and miR-210-3p upregulation induced TGF-β expression, indicating that hypoxia-induced HIF-1α activity upregulated TGF-β via miR-210-3p upregulation. Hypoxia-induced miR-210-3p activity was found to promote EMT by upregulating TGF-β, which subsequently enhanced the invasive ability in U87-MG cells. We further confirmed that miR-210-3p induced chemoresistance to TMZ in U87-MG cells via TGF-β upregulation under hypoxic conditions. CONCLUSION: These results help to reveal the potential regulatory mechanisms of hypoxia-induced miR-210-3p expression that affect malignant behaviors and chemoresistance via TGF-β upregulation in glioma cells.