title: microRNA expression pattern modulates temozolomide response in GBM tumors with cancer stem cells.
abstract: Temozolomide (TMZ) is widely used to treat glioblastoma multiforme (GBM). Although the MGMT gene methylation status is postulated to correlate with TMZ response, some patients with a methylated MGMT gene still do not benefit from TMZ therapy. Cancer stem cells (CSCs) may be one of the causes of therapeutic resistance, but the molecular mechanism underlying this resistance is unclear. microRNA (miRNA) deregulation has been recognized as another chemoresistance modulating mechanism. Thus, we aimed to evaluate the miRNA expression patterns associated with chemoresistance that is dependent on the CSC status in GBM tumors to identify therapeutic biomarkers. CSCs were identified in 5 of 20 patients' tumor tissues using magnetic separation. CSC (+) tumors displayed a significant induction of CpG island methylation in the MGMT gene promoter (p = 0.009). Using real-time reverse transcription polymerase chain reaction (qRT-PCR), 9 miRNAs related to GBM (mir-181b, miR-153, miR-137, miR-145, miR-10a, miR-10b, let-7d, miR-9, and miR-455-3p), which are associated with cell cycle and invasion was analyzed in tumor samples. Low miR-181b and high miR-455-3p expression levels were detected (p = 0.053, p = 0.004; respectively) in CSC (+) tumors. Analysis revealed a significant correlation between miR-455-3p expression and Smad2 protein levels as analyzed by immunohistochemistry in CSC (+) tumors (p = 0.002). Thus, miR-455-3p may be involved in TMZ resistance in MGMT methylated CSC (+) GBM patients. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for GBM treatment and new directions for the development of anticancer drugs.
authors.affiliation: Department of Medical Biology, Medical Faculty, Uludag University, Bursa, Turkey.
authors.forename: Gulcin
authors.initials: G
authors.lastname: Tezcan
authors.forename: Berrin
authors.initials: B
authors.lastname: Tunca
authors.forename: Ahmet
authors.initials: A
authors.lastname: Bekar
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.forename: Anna Sophie
authors.initials: AS
authors.lastname: Berghoff
authors.forename: Unal
authors.initials: U
authors.lastname: Egeli
authors.forename: Gulsah
authors.initials: G
authors.lastname: Cecener
authors.forename: Gerda
authors.initials: G
authors.lastname: Ricken
authors.forename: Ferah
authors.initials: F
authors.lastname: Budak
authors.forename: Mevlut Ozgur
authors.initials: MO
authors.lastname: Taskapılıoglu
authors.forename: Hasan
authors.initials: H
authors.lastname: Kocaeli
authors.forename: Sahsine
authors.initials: S
authors.lastname: Tolunay
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D015331:Cohort Studies; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015996:Survival Rate / Q000639:trends; D000077204:Temozolomide; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D035683:MicroRNAs; D003606:Dacarbazine; D000077204:Temozolomide