{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:48:00Z","timestamp":1789084080187,"version":"build-2803163510"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The General Program (Key Program, Major Research Plan) of National Natural Science Foundation of China","award":["82074298"],"award-info":[{"award-number":["82074298"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>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-1\u03b1 expression with TGF-\u03b2 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.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>We found that miR-210-3p was induced by a mechanism dependent on the hypoxia-induced transcriptional activity of HIF-1\u03b1. Then we established a positive association between the HIF-1\u03b1 and TGF-\u03b2 expression levels, and miR-210-3p upregulation induced TGF-\u03b2 expression, indicating that hypoxia-induced HIF-1\u03b1 activity upregulated TGF-\u03b2 via miR-210-3p upregulation. Hypoxia-induced miR-210-3p activity was found to promote EMT by upregulating TGF-\u03b2, 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-\u03b2 upregulation under hypoxic conditions.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>These results help to reveal the potential regulatory mechanisms of hypoxia-induced miR-210-3p expression that affect malignant behaviors and chemoresistance via TGF-\u03b2 upregulation in glioma cells.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0253522","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T17:50:18Z","timestamp":1625161818000},"page":"e0253522","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":42,"title":["MicroRNA-210-3p is transcriptionally upregulated by hypoxia induction and thus promoting EMT and chemoresistance in glioma 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tumors","volume":"472","author":"H Ohgaki","year":"2009","journal-title":"Methods Mol Biol"},{"key":"pone.0253522.ref002","doi-asserted-by":"crossref","first-page":"8259","DOI":"10.1158\/0008-5472.CAN-10-0604","article-title":"Functional microRNA is transferred between glioma cells","volume":"70","author":"M Katakowski","year":"2010","journal-title":"Cancer Res"},{"key":"pone.0253522.ref003","doi-asserted-by":"crossref","first-page":"7056","DOI":"10.1158\/0008-5472.CAN-13-0194","article-title":"A novel EGFR isoform confers increased invasiveness to cancer cells","volume":"73","author":"M Zhou","year":"2013","journal-title":"Cancer Res"},{"key":"pone.0253522.ref004","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1634\/theoncologist.13-S3-21","article-title":"Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis","volume":"3","author":"P Vaupel","year":"2008","journal-title":"Oncologist 13 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progression","volume":"347","author":"MK Wendt","year":"2012","journal-title":"Cell Tissue Res"},{"key":"pone.0253522.ref024","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/sj.cdd.4402310","article-title":"A microRNA component of the hypoxic response","volume":"15","author":"R Kulshreshtha","year":"2008","journal-title":"Cell Death Differ"},{"key":"pone.0253522.ref025","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1172\/JCI45105","article-title":"The cellular response to hypoxia: tuning the system with microRNAs","volume":"120","author":"J Loscalzo","year":"2010","journal-title":"J Clin Invest"},{"key":"pone.0253522.ref026","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/j.1750-3639.2010.00443.x","article-title":"Selective inhibition of early\u2014but not late\u2014expressed HIF-1alpha is neuroprotective in rats after focal ischemic brain damage","volume":"21","author":"SH Yeh","year":"2011","journal-title":"Brain 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