LncRNA GAS5 regulates ischemic stroke as a competing endogenous RNA for miR-137 to regulate the Notch1 signaling pathway

Biochem Biophys Res Commun. 2018 Jan 29;496(1):184-190. doi: 10.1016/j.bbrc.2018.01.022. Epub 2018 Jan 4.

Abstract

Ischemic stroke is related to a variety of physiological and pathological processes including autophagy and apoptosis. Growth arrest-specific 5 (GAS5), a long non-coding RNA (lncRNA), is known to negatively regulate cell survival and plays a key role in the pathogenesis of numerous diseases. However, the function and molecular mechanism of lncRNA GAS5 in ischemic stroke have not been reported. Real-time PCR was used to detect GAS5 and microRNA-137 (miR-137) expression in the brain tissues of mice underwent middle cerebral artery occlusion (MCAO) surgery and oxygen-glucose deprivation (OGD)-treated mouse primary brain neurons. Gain- or loss-of-function approaches were used to manipulate GAS5, miR-137, and Notch1. The mechanism of GAS5 in ischemic stroke was evaluated both in vivo and in vitro via bioinformatics analysis, MTT, flow cytometry, luciferase assay, RNA immunoprecipitation, and Western blot. GAS5 level was up-regulated and negatively correlated with miR-137 expression in MACO-injured brain and in OGR-stimulated primary brain neurons. GAS5 siRNA notably increased the cell viability, suppressed the activation of caspase-3 and cell apoptosis in neurons subjected to OGD. Furthermore, we also found that GAS5 functioned as a competing endogenous RNA (ceRNA) for miR-137 to regulate the de-repression of its endogenous target Notch1 and decrease neuron survival through inactivation of the Notch1 signaling pathway. Taken together, these findings indicate that GAS5 may promote the progression of ischemic stroke through acting as a ceRNA for miR-137 to mediate the Notch1 signaling pathway, which contributes to an extensive understanding of ischemic stroke and may provide novel therapeutic options for this disease.

Keywords: Competing endogenous RNA; Ischemic stroke; LncRNA GAS5; Notch1 signaling pathway; miR-137.

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Cell Survival
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Neurons / metabolism*
  • Neurons / pathology
  • RNA / metabolism*
  • RNA, Long Noncoding / metabolism*
  • Receptor, Notch1 / metabolism*
  • Signal Transduction
  • Stroke / metabolism*
  • Stroke / pathology

Substances

  • MIRN137 microRNA, mouse
  • MicroRNAs
  • Notch1 protein, mouse
  • RNA, Long Noncoding
  • Receptor, Notch1
  • long non-coding RNA GAS5, mouse
  • RNA