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Oncol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Glioblastoma multiforme (GBM) is one of the deadliest tumors, which is involved in numerous dysregulated microRNAs including miR-137. However, the mechanism of how miR-137 suppression associated with cancer progression and chemoresistance still remains to be elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Quantitative reverse transcriptase-PCR (qRT-PCR), DNA methylation analysis, cell proliferation assay, flow cytometric analysis, invasion assay, <jats:italic>in situ<\/jats:italic> tumor formation experiment were performed to test the expression levels and functions of miR-137 in GBM. Bioinformatics analysis, luciferase reporter assay, qRT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry assay were used to identify and verify the target of miR-137.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that miR-137 was downregulated in primary and recurrent GBM compared with normal brain tissues. Overexpression of miR-137 inhibited cell invasion and enhanced cell chemosensitivity to temozolomide (TMZ) by directly targeting low-density lipoprotein receptor-related protein 6 (LRP6) in GBM. Forced expression of LRP6 cDNA without its 3\u2019-UTR region partly restored the effects of miR-137 <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Hypoxia-induced miR-137 methylation was responsible for the miR-137 suppression, leading to the cell chemoresistance and poor prognosis of GBM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings demonstrated the detailed molecular mechanism of miR-137 in regulating GBM growth and chemoresistance in hypoxia microenvironment, suggesting the potentiality of miR-137 as a therapeutic target for GBM.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2020.611699","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T05:19:21Z","timestamp":1614230361000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6"],"prefix":"10.3389","volume":"10","author":[{"given":"Dong-Mei","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiu-Dan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gui-Ning","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Xing","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Hui","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhu-Mei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104390","article-title":"miR-140 targeting CTSB signaling suppresses the mesenchymal transition and enhances temozolomide cytotoxicity in glioblastoma multiforme","volume":"147","author":"Ho","year":"2019","journal-title":"Pharmacol Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.129","article-title":"MiR-181b modulates EGFR-dependent VCAM-1 expression and monocyte adhesion in glioblastoma","volume":"36","author":"Liu","year":"2017","journal-title":"Oncogene"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nou084","article-title":"MiR-124 governs glioma growth and angiogenesis and enhances chemosensitivity by targeting R-Ras and N-Ras","volume":"16","author":"Shi","year":"2014","journal-title":"Neuro-oncology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1038\/s41419-018-1176-7","article-title":"Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a\/Bad\/Bax axis","volume":"9","author":"Ge","year":"2018","journal-title":"Cell Death Dis"},{"key":"B6","article-title":"Role of micro-RNA (miRNA) in pathogenesis of glioblastoma","volume":"19","author":"Luo","year":"2015","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.18388\/abp.2015_1072","article-title":"miRNA Multiplayers in glioma. 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