title: MicroRNA-183 upregulates HIF-1α by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells.
abstract: MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and contribute to cell proliferation, differentiation and metabolism. Our previous study revealed the extensive modulation of a set of miRs in malignant glioma. In that study, miR microarray analysis demonstrated the upregulation of microRNA-183 (miR-183) in glioblastomas. Therefore, we examined the expression levels of miR-183 in various types of gliomas and the association of miR-183 with isocitrate dehydrogenase 2 (IDH2), which has complementary sequences to miR-183 in its 3'-untranslated region (3'UTR). In present study, we used real-time PCR analysis to demonstrate that miR-183 is upregulated in the majority of high-grade gliomas and glioma cell lines compared with peripheral, non-tumorous brain tissue. The mRNA and protein expression levels of IDH2 are downregulated via the overexpression of miR-183 mimic RNA in glioma cells. Additionally, IDH2 mRNA expression is upregulated in glioma cells expressing anti-miR-183. We verified that miR-183 directly affects IDH2 mRNA levels in glioma cells using luciferase assays. In malignant glioma specimens, the expression levels of IDH2 were lower in tumors than in the peripheral, non-tumorous brain tissues. HIF-1α levels were upregulated in glioma cells following transfection with miR-183 mimic RNA or IDH2 siRNA. Moreover, vascular endothelial growth factor and glucose transporter 1, which are downstream molecules of HIF-1α, were upregulated in cells transfected with miR-183 mimic RNA. These results suggest that miR-183 upregulation in malignant gliomas induces HIF-1α expression by targeting IDH2 and may play a role in glioma biology.
authors.affiliation: Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasayama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakamizo
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nishihara
authors.forename: Katsu
authors.initials: K
authors.lastname: Mizukawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kohta
authors.forename: Junji
authors.initials: J
authors.lastname: Koyama
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyake
authors.forename: Masaaki
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Kohkichi
authors.initials: K
authors.lastname: Hosoda
authors.forename: Eiji
authors.initials: E
authors.lastname: Kohmura
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; C533449:MIRN183 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase