Construction of a circRNA - Mediated ceRNA Network Reveals Novel Biomarkers for Aortic Dissection

Abstract Background Aortic dissection (AD) is a rare and lethal disorder with its genetic basis remains largely unknown. Many studies have confirmed that circular RNAs (circRNAs) play important roles in various physiological and pathological processes. However, the roles of circRNAs in AD are still unclear and need further investigation. The present study aimed to elucidate the underlying molecular mechanisms of circRNAs regulation in aortic dissection based on the circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network. Methods Expression profiles of circRNAs (GSE97745), miRNAs (GSE92427), and mRNAs (GSE52093) were downloaded from Gene Expression Omnibus (GEO) databases, and the differentially expressed RNAs (DERNAs) were subsequently identified in AD by bioinformatics analysis. Further bioinformatics analyses, including circRNA-miRNA-mRNA ceRNA network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, were used to predict the potential functions of circRNA-associated ceRNA regulatory network. RNA was isolated from human arterial blood samples after which quantitative real-time PCR (qRT-PCR) was performed to confirm the DERNAs. Results We identified 14 (5 up-regulated and 9 down-regulated) differentially expressed circRNAs (DEcircRNAs), 17 (8 up-regulated and 9 down-regulated) differentially expressed miRNAs (DEmiRNAs) and 527 (297 up-regulated and 230 down-regulated) differentially expressed mRNAs (DEmRNAs) when AD samples were compared with normal ascending aorta samples (adjusted P -value < 0.05 and | log2FC |> 1.0). KEGG pathway analysis indicated that DEmRNAs were related to focal adhesion and extracellular matrix (ECM) receptor interaction signaling pathways. Simultaneously, the present study successfully constructed a ceRNA regulatory network based on 1 circRNAs (hsa_circRNA_082317), 1 miRNAs (hsa-miR-149-3p) and 10 mRNAs (MLEC, ENTPD7, SLC16A3, SLC7A8, TBC1D16, PAQR4, MAPK13, PIK3R2, ITGA5, SERPINA1) in AD. Furthermore, qRT-PCR demonstrated that hsa_circRNA_082317 andα5 integrin (ITGA5) were significantly up-regulated in AD (n = 3), and hsa-miR-149-3p was dramatically down-regulated in AD (n = 3). The expression of hsa-miR-149-3p target mRNA, ITGA5, was positively modulated by hsa_circRNA_082317. Conclusion This is the first study to demonstrate the circRNA-associated ceRNA regulatory network is altered in AD, implying that circRNAs may play important roles in regulating the onset and progression of AD and thus may serve as potential biomarkers for the diagnosis and treatment of AD.