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MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells

  • Molecular Toxicology
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Abstract

MicroRNAs (miRNAs) can regulate cell survival and death by targeting apoptosis-related gene expression. miR-210 is one of the most hypoxia-sensitive miRNAs. In this study, we evaluated the roles of miR-210 in hypoxia-induced insults to neural cells. Treatment of neuro-2a cells with oxygen/glucose deprivation (OGD) induced cell apoptosis in a time-dependent manner. In parallel, OGD time-dependently increased cellular miR-210 levels. Knocking down miR-210 expression using specific antisenses significantly attenuated OGD-induced neural apoptosis. Concurrently, OGD increased hypoxia-inducible factor (HIF)-1α mRNA and protein syntheses. Pretreatment with YC-1, an inhibitor of HIF-1α, reduced OGD-caused cell death. Sequentially, OGD specifically decreased antiapoptotic Bcl-2 mRNA and protein levels in neuro-2a cells. A search by a bioinformatic approach revealed that miR-210-specific binding elements exist in the 3′-untranslated region of Bcl-2 mRNA. Application of miR-210 antisenses simultaneously alleviated OGD-involved inhibition of Bcl-2 mRNA expression. In comparison, overexpression of miR-210 synergistically diminished OGD-caused inhibition of Bcl-2 mRNA expression and consequently induced greater cellular insults. Taken together, this study shows that OGD can induce miR-210 expression through activating HIF-1α. And miR-210 can mediate hypoxia-induced neural apoptosis by targeting Bcl-2.

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Acknowledgments

This project was supported by grants from the Chi-Mei Medical Center (100CM-TMU-13-2), the Department of Health (DOH101-TD-C-111-008), and the National Science Council (98-2314-B-038-002-MY3), Taipei, Taiwan. The authors express their gratitude to Ms. Yi-Ling Lin and Ms. Ivy Tsai for technical support and data collection during the experiments.

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Authors and Affiliations

  1. Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan

    Chung-Ching Chio

  2. Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan

    Chung-Ching Chio, Jia-Wei Lin, Wen-Ta Chiu, Yuan-Hung Wang & Ruei-Ming Chen

  3. Department of Neurology, Yuan’s General Hospital, Kaohsiung, Taiwan

    Heien-An Cheng

  4. Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan

    Jhi-Joung Wang & Chung-Hsi Hsing

  5. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Xing St., Taipei, 110, Taiwan

    Ruei-Ming Chen

  6. Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, 250 Wu-Xing St., Taipei, 110, Taiwan

    Ruei-Ming Chen

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  1. Chung-Ching Chio
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  2. Jia-Wei Lin
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Correspondence to Ruei-Ming Chen.

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Chio, CC., Lin, JW., Cheng, HA. et al. MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells. Arch Toxicol 87, 459–468 (2013). https://doi.org/10.1007/s00204-012-0965-5

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  • DOI: https://doi.org/10.1007/s00204-012-0965-5

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