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MicroRNA-183 upregulates HIF-1α by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells

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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.

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Acknowledgments

We thank Mitsuharu Endo and Ryosuke Doi (Department of Physiology and Cell Biology, Kobe University, Japan) for helping with the luciferase reporter assays. We also thank Mariko Ueda for helping with the immunocytochemical analysis. This work was supported in part by a Grant-in-Aid for Scientific Research to Takashi Sasayama (22591610) and Katsu Mizukawa (22791344) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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None declared.

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Authors and Affiliations

  1. Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Hirotomo Tanaka, Takashi Sasayama, Kazuhiro Tanaka, Satoshi Nakamizo, Katsu Mizukawa, Masaaki Kohta, Junji Koyama, Shigeru Miyake, Masaaki Taniguchi, Kohkichi Hosoda & Eiji Kohmura

  2. Department of Neurosurgery, Nishi-Kobe Medical Center, Kobe, Japan

    Masamitsu Nishihara

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  1. Hirotomo Tanaka
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Correspondence to Takashi Sasayama.

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Tanaka, H., Sasayama, T., Tanaka, K. et al. MicroRNA-183 upregulates HIF-1α by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells. J Neurooncol 111, 273–283 (2013). https://doi.org/10.1007/s11060-012-1027-9

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  • DOI: https://doi.org/10.1007/s11060-012-1027-9

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