Bioinformatic Analysis of Potential microRNAs in Ischemic Stroke

https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.023Get rights and content

Background

MicroRNAs (miRNAs) are part of the brain's response to ischemia. This study aimed to screen potential miRNAs for the prediction and novel treatments of ischemic stroke.

Methods

Two mRNA and 1 miRNA microarray expression profile data were downloaded from the Gene Expression Omnibus database. Then, differentially expressed mRNAs and miRNAs were identified. Based on the miRNA–target pairs predicted, an miRNA–target interaction network was established. Bioinformatics analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment) was applied to interpret the function of the miRNA targets.

Results

In total, 16 differentially expressed miRNAs and 1345 differentially expressed genes were identified in ischemic stroke, respectively. Importantly, 445 miRNA–target pairs with an inverse correlation of expression were obtained, and the miRNA functional synergistic network was generated. Two miRNAs (miR-145 and miR-122) may represent potential biomarkers in ischemic stroke by being involved in the process of postischemic neuronal damage and thrombosis, respectively. Three novel miRNAs (miR-99b, miR-542-3p, and miR-455-5p) were deregulated, suggesting their roles in the pathological processes of ischemic stroke. Functional annotation indicated that apoptotic signaling cascades play an important role in patients with ischemic stroke.

Conclusion

miR-145 and miR-122 represent new biomarkers and underlying targets for the prevention and treatment of ischemic stroke.

Introduction

Ischemic stroke represents one of the leading causes of serious long-term disability and mortality worldwide, which is characterized by cerebral ischemia.1, 2 Up to now, ischemic stroke is diagnosed based mainly on the results from clinical examination, computed tomography and magnetic resonance imaging, and blood protein analyses, and thrombolysis is the only efficacious treatment for ischemic stroke.3 Ischemic stroke is considered as a highly complex polygenic disease with multiple underlying risk factors, such as hypertension, atherosclerosis, type 2 diabetes, smoking, and alcohol consumption.4

MicroRNAs (miRNAs) can bind to their target mRNAs, resulting in degradation and/or translational repression of the transcript. The altered miRNA expression can exert effects on many target mRNAs and result in diverse functional consequences. Many studies have been carried out to show the vital role of miRNAs in the progression of cerebral ischemia. Moreover, growing evidence has suggested that alteration of miRNAs plays critical roles in the pathologies of ischemic stroke.5 It was reported that miRNA may play an important regulatory role in the early cell stress response to ischemia in the brain and in the immune system and vasculature.6 Previous studies indicated that miRNAs are dysregulated in the blood and brain of rodent ischemic stroke and human stroke patients.7, 8, 9 The significance of several miRNAs in ischemic brain damage has been evaluated. miR-15a is important in the pathogenesis of ischemic vascular injury.10 Downregulation of miR-497 can reduce infarct and improve neurological deficits.11 It has been shown that miR-210 is positively correlated with better prognosis in stroke patients.12 Even so, the specificity to acute stroke pathology has not been established.

The dysregulation of genes in ischemic stroke is most likely regulated by miRNA. Hence, additional study is required to better understand miRNAs and their regulation of genes and pathways involved in ischemic stroke. To investigate this issue, we performed an integrated analysis of the miRNA and mRNA expression profiles of ischemic stroke. Based on the miRNA–target pairs predicted, a global miRNA–target regulatory network was constructed, which may further explain the regulatory mechanism of miRNAs, provide novel targeted therapeutic strategies against the affected patients, and improve ischemic stroke outcome.

Section snippets

Dataset Collection

The Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) served as a public repository for gene expression datasets,13 and it was used to obtain mRNA and miRNA expression profiling studies in ischemic stroke. The following keywords were used: ([“ischemia” {MeSH Terms} or ischemic {All Fields}] and [“stroke” {MeSH Terms} or stroke {All Fields}]) and “Homo sapiens” (porgn) and “gse” (Filter). Moreover, only the microarray studies were retained for further analysis. The basic

Differentially Expressed miRNAs and mRNAs in Ischemic stroke

According to inclusion criteria, 2 mRNA expression profiling studies (GSE22255 and GSE16561) and 1 miRNA expression profiling study (GSE55937) were obtained. In total, there were 68 normal samples and 83 patient samples, respectively (Table 1). After normalization of the original miRNA and mRNA expression data, we performed differentially expressed analysis between ischemic stroke and normal control samples. Finally, 16 miRNAs were regarded as significantly differentially expressed with P

Discussion

Endogenous circulating miRNAs are stable and have emerged as vital regulators in many physiological and pathological processes. Accumulating evidence has suggested that miRNAs have constituted excellent biomarkers for different human diseases.19 In the present study, we sought to scrutinize the effects of miRNAs by integrated analysis of 2 mRNA expression profiling and 1 miRNA expression profiling obtained from the GEO database. Based on the results from miRNA analysis, there were only 4

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