miR-195, miR-455-3p and miR-10a( *) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells.
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.
Ujifuku
Kenta
K
Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Japan.
Mitsutake
Norisato
N
Takakura
Shu
S
Matsuse
Michiko
M
Saenko
Vladimir
V
Suzuki
Keiji
K
Hayashi
Kentaro
K
Matsuo
Takayuki
T
Kamada
Kensaku
K
Nagata
Izumi
I
Yamashita
Shunichi
S
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
D018906:Antineoplastic Agents, Alkylating; D017931:DNA Primers; D035683:MicroRNAs; D009838:Oligodeoxyribonucleotides; D003606:Dacarbazine; D000077204:Temozolomide