Aberrant expression of miR-153 is associated with overexpression of hypoxia-inducible factor-1α in refractory epilepsy.

Yaohua Li,Wei Wang,Yanping Jiang,Cheng Huang,Dong Zhou,Lei Chen,Peimin Feng

doi:10.1038/srep32091

Abstract

Evidence suggest that overexpression of hypoxia-inducible factor-1α (HIF-1α) is linked to multidrug resistance of epilepsy. Here we explored whether aberrant expression of HIF-1α is regulated by miRNAs. Genome-wide microRNA expression profiling was performed on temporal cortex resected from mesial temporal lobe epilepsy (mTLE) patients and age-matched controls. miRNAs that are putative regulator of HIF-1α were predicted via target scan and confirmed by real-time quantitative polymerase chain reaction (RT-qPCR). Mimics or miRNA morpholino inhibitors were transfected in astrocytes and luciferase reporter assay was applied to detect HIF-11α expression. Microarray profiling identified down-regulated miR-153 as a putative regulator of HIF-1α in temporal cortex resected from surgical mTLE patients. RT-qPCR confirmed down-regulation of miR-153 in plasma of mTLE patients in an independent validation cohort. Knockdown of miR-153 significantly enhanced expression of HIF-1α while forced expression of miR-153 dramatically inhibited HIF-1α expression in pharmacoresistant astrocyte model. Luciferase assay established that miR-153 might inhibit HIF-1α expression via directly targeting two binding sites in the 3′UTR region of HIF-1α transcript. These data suggest that down-regulation of miR-153 may contribute to enhanced expression of HIF-1α in mTLE and serve as a novel biomarker and treatment target for epilepsy.

Highlights

MiRNA expressed in temporal cortex, 65 miRNAs were down-regulated and 29 miRNAs were up-regulated in Mesial temporal lobe epilepsy (mTLE) patients with a fold change >1
The key finding of our study is that miR-153 is significantly down-regulated in both temporal cortex tissue and plasma of patients with mTLE
Overexpression of multidrug resistance gene 1 (MDR1), P-gp in brain astrocytes decreases accumulation of anti-epileptic drugs (AEDs) in the brain, which has been widely accepted as a crucial factor in drug-resistant epilepsy[25,26]

Summary

Introduction

Recent study suggested that expression levels of numerous miRNAs are significantly dysregulated after status epilepticus in rat[20]. This raises the possibility that abnormally expressed miRNAs which contribute to the pathogenesis of epilepsy and enhanced expression of HIF-1αcould be, at least in part, caused by loss of expression of some regulatory miRNAs. To examine the possible role of miRNA in refractory epilepsy, we performed a genome-wide miRNA expression profiling studies to identify aberrantly expressed miRNAs in temporal cortex tissues isolated from mTLE patients. We validated aberrant expression of these miRNAs in a larger validation cohort, and used functional assays to investigate their roles in regulating HIF-1αexpression. These findings have largely extended the current concepts of mTLE pathogenesis to miRNA-mediated gene expression regulation

Methods

Results

Conclusion