title: MicroRNA-101 reverses temozolomide resistance by inhibition of GSK3β in glioblastoma.
abstract: Glioblastoma multiforme (GBM) is a chemotherapy-resistant brain tumor with limited treatment options. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug currently employed in GBM. Although it is currently the most promising chemotherapy for GBM, resistance to TMZ is also common and accounts for many treatment failures. Therefore, understanding the underlying mechanisms that generate resistance is essential to develop more effective chemotherapies. Here, we show that microRNA-101 (miR-101) was significantly downregulated in TMZ-resistant GBM cells and human specimens. Instead, over-expression of miR-101 could sensitize resistant GBM cells to TMZ through downregulation of glycogen synthase kinase 3β (GSK3β). Moreover, we found that GSK3β inhibition could enhance TMZ effect through repression of MGMT via promoter methylation. Importantly, decreased expression of miR-101 is related to poor prognosis in patients with GBM, suggesting its potential role as a new prognostic marker in GBM. In conclusion, our study demonstrates that miR-101 can reverse TMZ resistance by inhibition of GSK3β in GBM, thus offer a novel and powerful strategy for GBM therapy.
authors: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China.|Department of Neurology, Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China.
authors: Tian
authors: T
authors: Tian
authors: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China.
authors: Ma
authors: M
authors: Mingyi
authors: Department of Medicine, Shangqiu Medical School, Shangqiu 476000, Henan Province, People's Republic of China.
authors: Xia
authors: X
authors: Qiu
authors: Department of Clinical Medicine, Shaoyang Medical College, Shaoyang 422000, Hunan Province, People's Republic of China.
authors: Yang
authors: Y
authors: Qiu
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: chemoresistance; glioblastoma; microRNA; prognosis; temozolomide