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Identification of potential novel biomarkers for abdominal aortic aneurysm based on comprehensive analysis of circRNA-miRNA-mRNA networks

ABSTRACT: Abdominal aortic aneurysm (AAA) is a life-threatening disorder and, therefore, investigation into its underlying mechanisms in light of the competing endogenous RNAs (ceRNAs) hypothesis has gradually increased. However, there is still lacking systematic analysis on AAA-associated circular RNA (circRNA)-microRNA (miRNA/miR)-messenger RNA (mRNA) interaction networks based on bioinformatics methods. The present study attempted to identify novel molecular biomarkers for AAA by profiling circRNA-miRNA-mRNA networks using three public microarray datasets (GSE7084, GSE57691 and GSE144431). A total of 135 differentially expressed genes (DEGs) and 142 differentially expressed circRNAs were detected using the limma R package with the statistical threshold of P<0.05 and |log2fold change (FC)| >1.5. In addition, 12 circRNA-miRNA-mRNA axes were identified to construct upregulated and downregulated ceRNA networks using Cytoscape. Based on molecular complex detection algorithm, (hsa_circ_0057691/0092108/0006845/0082182)- miR-330-5p-calponin 1 (CNN1) and (hsa_circ_0061482/0011450/0008351/0004121)-miR-326-CD8a molecule (CD8A) were recognized as the center axes in ceRNA networks. Reverse transcription-quantitative PCR results verified the significant downregulation of CNN1 and upregulation of CD8A in human AAA tissues (P<0.05). In addition, four upregulated circRNA/mRNA axes, and five downregulated circRNA/mRNA axes were revealed to have possible biological functions in the pathogenesis of AAA using the Cytoscape software. Receiver operating characteristic analysis demonstrated the accuracy of these nine DEGs involved in these axes for AAA diagnosis with area under the curves >0.80. The present study revealed novel circRNA-miRNA-mRNA networks associated with AAA, especially for CNN1 and CD8A axes with the potential function of ‘focal adhesion’ and ‘immune response’, respectively. Overall, the present findings may provide evidence to explore the implicated ceRNAs in the molecular mechanisms and as novel biomarkers for AAA.

SUBMITTER: Li T

PROVIDER: S-EPMC8561771 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAbdominal aortic aneurysm (AAA) is a progressive cardiovascular disease, which is a permanent and localized dilatation of the abdominal aorta with potentially fatal consequence of aortic rupture. Dysregulation of circRNAs is correlated with the development of various pathological events in cardiovascular diseases. However, the function of circRNAs in abdominal aortic aneurysm (AAA) is unknown and remains to be explored. This study is aimed at determining the regulatory mechanisms of circRNAs in AAAs. This study was aimed at exploring the underlying molecular mechanisms of abdominal aortic aneurysms based on the competing endogenous RNA (ceRNA) regulatory hypothesis of circRNA, miRNA, and mRNA.MethodsThe expression profiles of circRNAs (GSE144431), miRNAs (GSE62179), and mRNAs (GSE7084, GSE57691, and GSE47472) in human tissue sample from the aneurysm group and normal group were obtained from the Gene Expression Omnibus database, respectively. The circRNA-miRNA-mRNA network was constructed by using Cytoscape 3.7.2 software; then, the protein-protein interaction (PPI) network was constructed by using the STRING database, and the hub genes were identified by using the cytoHubba plug-in. The circRNA-miRNA-hub gene regulatory subnetwork was formed to understand the regulatory axis of hub genes in AAAs.ResultsThe present study identified 40 differentially expressed circRNAs (DECs) in the GSE144431, 90 differentially expressed miRNAs (DEmiRs) in the GSE62179, and 168 differentially expressed mRNAs (DEGs) with the same direction regulation (130 downregulated and 38 upregulated) in the GSE7084, GSE57691, and GSE47472 datasets identified regarding AAAs. The miRNA response elements (MREs) of three DECs were then predicted. Four overlapping miRNAs were obtained by intersecting the predicted miRNA and DEmiRs. Then, 17 overlapping mRNAs were obtained by intersecting the predicted target mRNAs of 4 miRNAs with 168 DEGs. Furthermore, the circRNA-miRNA-mRNA network was constructed through 3 circRNAs, 4 miRNAs, and 17 mRNAs, and three hub genes (SOD2, CCR7, and PGRMC1) were identified. Simultaneously, functional enrichment and pathway analysis were performed within genes in the circRNA-miRNA-mRNA network. Three of them (SOD2, CCR7, and PGRMC1) were suggested to be crucial based on functional enrichment, protein-protein interaction, and ceRNA network analysis. Furthermore, the expression of SOD2 and CCR7 may be regulated by hsa_circ_0011449/hsa_circ_0081968/hsa-let-7f-5p; the expression of PGRMC1 may be regulated by hsa_circ_0011449/hsa_circ_0081968-hsa-let-7f-5p/hsa-let-7e-5p.ConclusionIn conclusion, the ceRNA interaction axis we identified may be an important target for the treatment of abdominal aortic aneurysms. This study provided further understanding of the potential pathogenesis from the perspective of the circRNA-related competitive endogenous RNA network in AAAs.

Project description:BackgroundAbdominal aortic aneurysm (AAA) is a disease commonly seen in the elderly. The aneurysm diameter increases yearly, and the larger the AAA the higher the risk of rupture, increasing the risk of death. However, there are no current effective interventions in the early stages of AAA.MethodsFour gene expression profiling datasets, including 23 normal artery (NOR) tissue samples and 97 AAA tissue samples, were integrated in order to explore potential molecular biological targets for early intervention. After preprocessing, differentially expressed genes (DEGs) between AAA and NOR were identified using LIMMA package. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were conducted using the DAVID database. The protein-protein interaction network was constructed and hub genes were identified using the STRING database and plugins in Cytoscape. A circular RNA (circRNA) profile of four NOR tissues versus four AAA tissues was then reanalyzed. A circRNA-miRNA-mRNA interaction network was constructed after predictions were made using the Targetscan and Circinteractome databases.ResultsA total of 440 DEGs (263 up-regulated and 177 down-regulated) were identified in the AAA group, compared with the NOR group. The majority were associated with the extracellular matrix, tumor necrosis factor-α, and transforming growth factor-β. Ten hub gene-encoded proteins (namely IL6, RPS27A, JUN, UBC, UBA52, FOS, IL1B, MMP9, SPP1 and CCL2) coupled with a higher degree of connectivity hub were identified after protein-protein interaction network analysis. Our results, in combination with the results of previous studies revealed that miR-635, miR-527, miR-520h, miR-938 and miR-518a-5p may be affected by circ_0005073 and impact the expression of hub genes such as CCL2, SPP1 and UBA52. The miR-1206 may also be affected by circ_0090069 and impact RPS27A expression.ConclusionsThis circRNA-miRNA-mRNA network may perform critical roles in AAA and may be a novel target for early intervention.

Project description:BackgroundCircular RNA (circRNA) plays an important role in the regulation of gene expression and the occurrence of human diseases. However, studies on the role of circRNA in acute myocardial infarction (AMI) are limited. This study was performed to explore novel circRNA-related regulatory networks in AMI, aiming to better understand the molecular mechanism of circRNAs involvement in AMI and provide basis for further scientific research and clinical decision-making.MethodsThe AMI-related microarray datasets GSE160717 (circRNA), GSE31568 (miRNA), GSE61741 (miRNA), and GSE24519 (mRNA) were obtained from the Gene Expression Omnibus (GEO) database. After differential expression analysis, the regulatory relationships between these DERNAs were identified by online databases circBank, circInteractome, miRDB, miRWalk, Targetscan, and then two circRNA-miRNA-mRNA regulatory networks were constructed. Differentially expressed genes (DEGs) in this network were selected followed by enrichment analysis and protein-protein interaction (PPI) analysis. Hub genes were identified using Cytohubba plug-in of Cytoscape software. Hub genes and hub gene-related miRNAs were used for receiver operating characteristic curve (ROC) analysis to identify potential biomarkers. The relative expression levels of these biomarkers were further assessed by GSE31568 (miRNA) and GSE66360 (mRNA). Finally, on the basis of the above analysis, myocardial hypoxia model was constructed to verify the expression of Hub genes and related circRNAs.ResultsA total of 83 DEcircRNAs, 109 CoDEmiRNAs and 1204 DEGs were significantly differentially expressed in these datasets. The up-regulated circRNAs and down-regulated circRNAs were used to construct a circRNA-miRNA-mRNA regulatory network respectively. These circRNA-related DEGs were mainly enriched in the terms of "FOXO signaling pathway," "T cell receptor signaling pathway," "MAPK signaling pathway," "Insulin resistance," "cAMP signaling pathway," and "mTOR signaling pathway." The top 10 hub genes ATP2B2, KCNA1, GRIN2A, SCN2B, GPM6A, CACNA1E, HDAC2, SRSF1, ANK2, and HNRNPA2B1 were identified from the PPI network. Hub genes GPM6A, SRSF1, ANK2 and hub gene-related circRNAs hsa_circ_0023461, hsa_circ_0004561, hsa_circ_0001147, hsa_circ_0004771, hsa_circ_0061276, and hsa_circ_0045519 were identified as potential biomarkers in AMI.ConclusionIn this study, the potential circRNAs associated with AMI were identified and two circRNA-miRNA-mRNA regulatory networks were constructed. This study explored the mechanism of circRNA involvement in AMI and provided new clues for the selection of new diagnostic markers and therapeutic targets for AMI.

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Identification of potential novel biomarkers for abdominal aortic aneurysm based on comprehensive analysis of circRNA-miRNA-mRNA networks

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