title: miR-195, miR-455-3p and miR-10a( *) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells.
abstract: To identify microRNAs (miRNAs) specifically involved in the acquisition of temozolomide (TMZ) resistance in glioblastoma multiforme (GBM), we first established a resistant variant, U251R cells from TMZ-sensitive GBM cell line, U251MG. We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a( *) were the three most up-regulated miRNAs in the resistant cells. To investigate the functional role of these miRNAs in TMZ resistance, U251R cells were transfected with miRNA inhibitors consisting of DNA/LNA hybrid oligonucleotides. Suppression of miR-455-3p or miR-10a( *) had no effect on cell growth, but showed modest cell killing effect in the presence of TMZ. On the other hand, knockdown of miR-195 alone displayed moderate cell killing effect, and combination with TMZ strongly enhanced the effect. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs. In conclusion, our findings suggest that those miRNAs may play a role in acquired TMZ resistance and could be a novel target for recurrent GBM treatment.
authors.affiliation: Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Ujifuku
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
authors.forename: Shu
authors.initials: S
authors.lastname: Takakura
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsuse
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saenko
authors.forename: Keiji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsuo
authors.forename: Kensaku
authors.initials: K
authors.lastname: Kamada
authors.forename: Izumi
authors.initials: I
authors.lastname: Nagata
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D017931:DNA Primers; D035683:MicroRNAs; D009838:Oligodeoxyribonucleotides; D003606:Dacarbazine; D000077204:Temozolomide