title: miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1.
abstract: Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly with a high frequency. Glioblastoma stem cells (GSCs) causing resistance to drug therapy were considered to be one of key factors. The mechanisms underlying GSCs resistance to TMZ are not fully understood. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. Previous study showed that miR-125b was necessary for GSCs fission and for making stem cells insensitive to chemotherapy. Thus, exploring the functions and mechanisms of miR-125b action on TMZ-treated GSCs would be valuable. In this study, we found that miR-125b was up-regulated in TMZ-resistant cells, inhibition of which caused a marked increase of TMZ-induced cytotoxicity and apoptosis and a subsequent decrease in the resistance to TMZ in GSCs. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) was a direct target of miR-125b. Down-regulation of Bak1 inhibited TMZ-induced apoptosis and led to an increased resistance to TMZ. Restoring Bak1 expression recovered TMZ sensitivity on GSCs. Taken together; our data strongly support an important role for miR-125b on conferring TMZ resistance through targeting Bak1 expression.
authors.affiliation: Department of general surgery, The First People's Hospital of Kunshan affiliated with Jiangsu University, Suzhou, 215300, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Xingli
authors.initials: X
authors.lastname: Fu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wan
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Dongyi
authors.initials: D
authors.lastname: Jiang
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D000077204:Temozolomide; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C494772:BAK1 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D050998:bcl-2 Homologous Antagonist-Killer Protein; D003606:Dacarbazine; D000077204:Temozolomide