Construction of lncRNA-miRNA-mRNA networks reveals functional lncRNAs in abdominal aortic aneurysm.
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ABSTRACT:
SUBMITTER: Tian L
PROVIDER: S-EPMC6176170 | biostudies-literature | 2018 Nov
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.
| S-EPMC8589483 | biostudies-literature
Project description: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.
| S-EPMC8561771 | biostudies-literature
Project description:Psoriasis is a chronic inflammatory skin disorder that impairs the quality of life of affected patients. Emerging studies indicate that certain long non-coding RNAs (lncRNAs) have important roles in psoriasis. However, the exact functions of lncRNAs and their regulatory mechanisms as competitive endogenous RNAs (ceRNAs) in psoriasis have remained to be fully elucidated. In the present study, differentially expressed lncRNAs, microRNAs (miRNAs) and mRNAs were identified by analyzing public datasets, and a psoriasis-associated lncRNA-miRNA-mRNA network was constructed based on the ceRNA theory. Furthermore, previously validated abnormally expressed miRNAs in psoriasis were identified by a systematic literature search in the PubMed and Web of Science databases, and a specific miRNA-associated lncRNA-miRNA-mRNA sub-network was extracted. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using DAVID 6.8. A total of 253 lncRNAs, 106 miRNAs and 1,156 mRNAs were identified as being differentially expressed between psoriasis skin and healthy control skin. The present study identified two key lncRNAs that may potentially have a role in the pathogenesis of psoriasis: AL035425.3 and Prader Willi/Angelman region RNA 6. This integrative analysis enhances the understanding of the molecular mechanism of psoriasis and may provide novel therapeutic targets for the treatment of psoriasis.
| S-EPMC6781786 | biostudies-literature
Project description:Background: Ovarian cancer (OC) is the most lethal malignancy in the female reproductive system. Growing evidences demonstrates that competing endogenous RNA (ceRNA) network play crucial roles in the occurrence and progression of tumors. Therefore, we aimed to explore and identify novel mRNA-miRNA-lncRNA ceRNA networks associated with prognosis of OC. Methods: The differentially expressed gene (DEGs) of four expression profiles datasets (GSE5438, GSE40595, GSE38666 and GSE26712) were collected from Gene Expression Omnibus (GEO) database and analyzed with NetworkAnalyst. Intersection of DEGs were further employed for Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis. Protein-protein interaction (PPI) network and hub genes of DEGs were also identified. The expression levels and survival analysis of the hub genes in OC and their upstream miRNAs and lncRNAs were performed by various bioinformatics databases. More importantly, ceRNA networks were constructed based on mRNA-miRNA-lncRNA in OC. Results: A total of 178 DEGs including 38 upregulated and 140 downregulated genes from intersected DEGs of four expression profiles were identified in OC. Functional enrichment analysis suggested that the commonly DEGs were enriched in regulating enzyme inhibitor activity, glycosaminoglycan and G protein-coupled receptor binding, cell morphogenesis, and involved in pathways including metabolic process, proteoglycans in cancer. Top 10 hub genes with higher connectivity degree were selected for subsequent expression and prognosis analysis. After take expression levels and prognostic roles of hub genes and their upstream miRNAs and lncRNAs in OC into consideration, 2 mRNAs (TACC3 and CXCR4), 2 miRNAs (hsa-miR-425-5p and hsa-miR-146a-5p) and 3 lncRNAs (FUT8-AS1, LINC00665 and LINC01535) were significantly associated with the poor prognosis of OC. The mRNA-miRNA-lncRNA networks (TACC3-hsa-miR-425-5p-FUT8-AS1 and CXCR4-hsa-miR-146a-5p-LINC00665/LINC01535) were eventually constructed in OC based on ceRNA mechanism. Conclusion: We successfully constructed novel ceRNA network associated with the prognosis of ovarian cancer, which may provide a new strategy for early diagnosis and therapeutic intervention of OC.
| S-EPMC7592000 | biostudies-literature
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.
| S-EPMC8711282 | biostudies-literature
Project description:BACKGROUND:A growing evidence suggests that long non-coding RNAs (lncRNAs) can function as a microRNA (miRNA) sponge in various diseases including oral cancer. However, the pathophysiological function of lncRNAs remains unclear. METHODS:Based on the competitive endogenous RNA (ceRNA) theory, we constructed a lncRNA-miRNA-mRNA network in oral cancer with the human expression profiles GSE74530 from the Gene Expression Omnibus (GEO) database. We used topological analysis to determine the hub lncRNAs in the regulatory ceRNA network. Then, function enrichment analysis was performed using the clusterProfiler R package. Clinical information was downloaded from The Cancer Genome Atlas (TCGA) database and survival analysis was performed with Kaplan-Meier analysis. RESULTS:A total of 238 potential co-dysregulated competing triples were obtained in the lncRNA-associated ceRNA network in oral cancer, which consisted of 10 lncRNA nodes, 41 miRNA nodes and 122 mRNA nodes. Additionally, we found lncRNA HCG22 exhibiting superior potential as a diagnostic and prognostic marker of oral cancer. CONCLUSIONS:Our findings provide novel insights to understand the ceRNA regulation in oral cancer and identify a novel lncRNA as a potential molecular biomarker.
| S-EPMC7310129 | biostudies-literature
Project description:Long non-coding RNAs (lncRNAs) play key roles in diverse biological processes. Moreover, the development and progression of cancer often involves the combined actions of several lncRNAs. Here we propose a multi-step method for constructing lncRNA-lncRNA functional synergistic networks (LFSNs) through co-regulation of functional modules having three features: common coexpressed genes of lncRNA pairs, enrichment in the same functional category and close proximity within protein interaction networks. Applied to three cancers, we constructed cancer-specific LFSNs and found that they exhibit a scale free and modular architecture. In addition, cancer-associated lncRNAs tend to be hubs and are enriched within modules. Although there is little synergistic pairing of lncRNAs across cancers, lncRNA pairs involved in the same cancer hallmarks by regulating same or different biological processes. Finally, we identify prognostic biomarkers within cancer lncRNA expression datasets using modules derived from LFSNs. In summary, this proof-of-principle study indicates synergistic lncRNA pairs can be identified through integrative analysis of genome-wide expression data sets and functional information.
| S-EPMC4694810 | biostudies-literature
Project description:BACKGROUND:Human skin cutaneous melanoma is the most common and dangerous skin tumour, but its pathogenesis is still unclear. Although some progress has been made in genetic research, no molecular indicators related to the treatment and prognosis of melanoma have been found. In various diseases, dysregulation of lncRNA is common, but its role has not been fully elucidated. In recent years, the birth of the "competitive endogenous RNA" theory has promoted our understanding of lncRNAs. METHODS:To identify the key lncRNAs in melanoma, we reconstructed a global triple network based on the "competitive endogenous RNA" theory. Gene Ontology and KEGG pathway analysis were performed using DAVID (Database for Annotation, Visualization, and Integration Discovery). Our findings were validated through qRT-PCR assays. Moreover, to determine whether the identified hub gene signature is capable of predicting the survival of cutaneous melanoma patients, a multivariate Cox regression model was performed. RESULTS:According to the "competitive endogenous RNA" theory, 898 differentially expressed mRNAs, 53 differentially expressed lncRNAs and 16 differentially expressed miRNAs were selected to reconstruct the competitive endogenous RNA network. MALAT1, LINC00943, and LINC00261 were selected as hub genes and are responsible for the tumorigenesis and prognosis of cutaneous melanoma. CONCLUSIONS:MALAT1, LINC00943, and LINC00261 may be closely related to tumorigenesis in cutaneous melanoma. In addition, MALAT1 and LINC00943 may be independent risk factors for the prognosis of patients with this condition and might become predictive molecules for the long-term treatment of melanoma and potential therapeutic targets.
| S-EPMC7523354 | biostudies-literature
Project description:Atherosclerosis is one of the most common clinical cardiovascular disorders. Accumulating evidence indicates that lncRNAs exert critical functions in atherosclerosis; however, their functional roles and regulatory mechanisms remain unclear. In this study, we induced atherosclerotic plaques in three rabbit carotid arteries through an atherogenic diet and balloon injury; three age-matched rabbits were fed normal chow and served as controls. We thoroughly investigated the RNA (mRNA, lncRNA and miRNA) expression profiles in atherosclerotic rabbit carotid models with deep RNA sequencing. We identified several significantly differentially expressed RNAs. The corresponding lncRNA-miRNA-mRNA network was constructed, and the significantly dysregulated network was selected. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that the mRNAs in the network were involved in leukocyte activation, cell proliferation, cell adhesion molecules and cytokine-cytokine receptor interaction. After rigorous screening, we obtained a differentially expressed lncRNA-miRNA-mRNA interaction network associated with atherosclerosis. In the network, XLOC_054118 and XLOC_030217 upregulate the CHI3L1, SOAT, CTSB and CAPG genes by competitively binding to the miRNA ocu-miR-96-5p. XLOC_062719 and XLOC_063297 upregulate CTSS, CTSB and EDNRA genes by competitively binding to the miRNA ocu-miR-185-5p.
| S-EPMC7041763 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since the first candidate gene studies were published 20 years ago, approximately 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. These studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, only when appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called contactin-3, which is located on chromosome 3p12.3. However, two follow-up studies could not replicate this association. Two other SNPs, which are located on chromosome 9p21 and 9q33, were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense ribonucleic acid that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute toward AAA pathogenesis.
| S-EPMC3058859 | biostudies-literature