Abstract
Recent studies have found that circular RNAs (circRNAs) play crucial roles not only in the normal growth and the development of different tissues and organs but also in the pathogenesis and progression of various disorders. However, the expression patterns and the function of circRNAs in acute ischemic stroke (AIS) in the South Chinese Han population are unclear. In the present study, RNA sequencing (RNA-seq) data was generated from 3 AIS patients and 3 healthy controls. The circRNAs were detected and identified by CIRI2 and Find_circ software. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were used to detect the expression of circRNAs. Meanwhile, the potential diagnostic value of the selected circRNAs for AIS was assessed by generating receiver operating characteristic (ROC) curve with area under curve (AUC). The bioinformatic analysis of the host genes of differentially expressed (DE) circRNAs was performed by gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, KOBAS for pathway analysis and regulatory network analysis. miRNA-circRNA and miRNA-mRNA interactions were predicted by using TargetScan, miRanda and starBase. CircRNA-miRNA-mRNA interaction networks were created with Cytoscape. Our result showed that there were 2270 DE circRNAs between AIS patients and healthy controls. Among them, 659 were found upregulated and 1611 were downregulated. Bioinformatic analysis showed that the DE circRNAs were related to the following biological processes: endocytosis, energy metabolism, apoptosis, FoxO signaling pathway, platelet activation, neurotrophin signaling pathway and VEGF signaling pathway, which may be associated with the pathological of AIS. Three randomly selected circRNAs were successfully validated by qRT‐PCR. The results show that hsa_circ_0005548 was significantly upregulated, while hsa_circ_0000607 and hsa_circ_0002465 were significantly downregulated in AIS. Furthermore, the AUC values for hsa_circ_005548, hsa_circ_0000607 and hsa_circ_0002465 were 0.51, 0.75 and 0.69, respectively, suggesting that hsa_circ_0000607 and hsa_circ_0002465 could be potential biomarkers for AIS. In addition, Bcl2 was predicted to be a direct target of miR-337-3p, and hsa_circRNA_0000607 was predicted to act as a sponge for miR-337-3p. Thus, hsa_circ_0000607 may be involved in AIS by regulating the miR-337-3p/Bcl2 axis. Collectively, our findings indicate that numerous dysregulated circRNAs may play pivotal functional roles in AIS and hsa_circ_0000607 may play a crucial role in the pathogenesis and progression of AIS by regulating the miR-337-3p/Bcl2 axis.
Highlights
Stroke is one of the leading causes of death and a major cause of long-term disability worldwide
The statistics for the known genes are shown in Fig. 1c: protein_coding accounts for 87.4%, others account for 10.0%, lincRNA accounts for 1%, antisense accounts for 0.8%, transcribed_unprocessed_pseudogene accounts for 0.3%, processed_transcript accounts for 0.3%, processed_pseudogene accounts for 0.1%, and IG_C_gene accounts for 0.1%
We focused on the miRNAs with the strongest relationships with the top six differentially expressed (DE) circRNAs, which were mainly predicted by starBase and miRanda software
Summary
Stroke is one of the leading causes of death and a major cause of long-term disability worldwide. Major progress in the diagnosis and treatment of acute ischemic stroke (AIS) has been reported in recent years, the mortality and long-term disability rates of IS are still high. CircMTO1 suppresses human hepatocellular carcinoma progression via acting as the sponge of miR-9 to promote the expression level of P21, indicating that circMTO1 may be a potential novel therapeutic target in human hepatocellular carcinoma treatment[12]. Another study manifested that the expression of circRNA HECTD1 was associated with risk, severity and recurrence of AIS14. These observations indicate that circRNAs have the potential to serve as novel diagnostic biomarkers and molecular therapeutic targets for AIS. Potential circRNA-miRNA-mRNA network targeting relationships were created by Cytoscape software based on the RNA-seq data and bioinformatic prediction results
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