Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway

Honglin Yan,Likun Gao,Jie Rao,Lina Zhao,Jingping Yuan,Wenxian Huang,Jiacai Ren

doi:10.1038/s41419-017-0047-y

Honglin Yan, Likun Gao + Show 5 more

Open Access

https://doi.org/10.1038/s41419-017-0047-y

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Abstract

Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been demonstrated as an important regulator in diverse human cancers. However, its function and regulatory mechanism in ischemic stroke remains largely unknown. Here, we report that MEG3 is physically associated with microRNA-21 (miR-21), while miR-21 is downregulated following ischemia in the ischemic core in vitro and in vivo, which is opposite to MEG3. Besides, overexpression of miR-21 protects oxygen–glucose deprivation and reoxygenation (OGD/R)-induced apoptotic cell death. Furthermore, MEG3 functions as a competing endogenous RNAs (ceRNAs) and competes with programmed cell death 4 (PDCD4) mRNA for directly binding to miR-21, which mediates ischemic neuronal death. Knockdown of MEG3 protects against ischemic damage and improves overall neurological functions in vivo. Thus, our data uncovers a novel mechanism of lncRNA MEG3 as a ceRNA by targeting miR-21/PDCD4 signaling pathway in regulating ischemic neuronal death, which may help develop new strategies for the therapeutic interventions in cerebral ischemic stroke.

Highlights

Stroke is an acute cerebrovascular disease caused by poor blood flow to the brain
Knockdown of maternally expressed gene 3 (MEG3) protected against ischemia and reperfusion (I/R)-induced ischemic brain damage and improved overall neurological functions. These findings indicate that Long non-coding RNA (lncRNA) MEG3 functions as a competing endogenous RNAs (ceRNAs) for miR-21 to regulate programmed cell death 4 (PDCD4) expression in ischemic neuronal death followed by reperfusion, which may inform new therapeutic strategies for ischemic insults
MEG3 is physically associated with miR-21 According to the recent study, ceRNAs, such as lncRNAs, could compete for binding to miRNAs through miRNA response elements (MREs), preventing the binding of miRNAs to target mRNAs25

Summary

Introduction

Stroke is an acute cerebrovascular disease caused by poor blood flow to the brain. 85% of all reported strokes are due to cerebral ischemia which occurs when an embolus or thrombus blocks the major cerebral artery resulting in cell death[1]. The only effective treatment of ischemic stroke is the application of tissue plasminogen activator (tPA)[2]. Due to the narrow therapeutic window (less than 4.5 h), strict indications for treatment and the risk of secondary hemorrhage, only a few stroke sufferers benefit from it. Failures in recovery of blood flow highlights the need for an alternative method for the treatment of cerebral ischemia[3]. During the first 3 days following cerebral

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