Identifying Interaction Clusters for MiRNA and MRNA Pairs in TCGA Network.
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ABSTRACT:
SUBMITTER: Dai X
PROVIDER: S-EPMC6770970 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Increasing evidence shows microRNAs (miRNAs) are engaged in hepatocelluar carcinoma (HCC). To identify novel feasible miRNA/mRNA pairs involved in hepatocarcinogenesis, an in-depth analysis of miRNomes in human non-tumor liver and HCC samples was carried out in this study. Firstly, differentially expressed miRNAs were obtained from deep sequencing of 15 liver samples, and verified in an independent data from The Cancer Genome Atlas (TCGA) database. Then, differentially expressed mRNA targets were selected from TCGA, and the differential miRNA/mRNA pairs with negative correlations were screened out. Finally, functional enrichment analysis was used to predict the functions of miRNA/mRNA pairs in HCC. In our study, 81 miRNA/mRNA pairs and 7 novel miRNAs were found. We constructed a hub interaction model with 9 miRNA/mRNA pairs to further investigate molecular mechanism of HCC. Survival analysis identified nine genes (hsa-miR-137, hsa-miR-490, BIRC5, TOP2A, CDC25C, IGF2BP1, IQGAP3, NCAPG and VIPR1) with significant influence on prognosis of HCC patients. In conclusion, the miRNA/mRNA pairs identified in our study may have some potential values to be further studied in progression, diagnosis and prognosis of HCC.
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Project description:Although considerable progress has been made in the molecular biology of Colorectal cancer (CRC), novel approaches are still required to uncover the detailed molecular mechanism of CRC. We aim to explore the potential negatively regulated miRNA-mRNA pairs and investigate their regulatory roles so as to elaborate the potential roles of the critical proteins in the signaling pathways enriched by the differential target genes of negatively regulated miRNA in CRC. Firstly, the differential miRNA-mRNA pairs were selected, followed by pairs of miRNA and their target genes. The obtained relationships were subjected to do functional enrichment analysis and those enriched in CRC pathways were chose to further construct a protein interaction network. Finally, we analyzed the regulatory roles of these relationships and constructed a regulatory network of negatively regulated miRNA and mRNA relationships. A total of 372 pairs of miRNA-mRNA were found and 108 target genes of miRNA were obtained. Three miRNAs including hsa-mir-23b, hsa-mir-365-1 and hsa-mir-365-2 showed significant influence on prognosis of CRC patients. To conclude, the miRNA/mRNA deregulations pairs identified in this study have high potentials to be further applied in diagnosis and treatment of CRC.
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Project description:DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage-induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA-mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2-miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis.
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Project description:Hepatoblastoma (HB) is a rare disease but nevertheless the most common hepatic tumor in the pediatric population. For patients with advanced HB, the prognosis is dismal and there are limited therapeutic options. Multiple microRNAs (miRNAs) were reported to be involved in HB development, but the miRNA-mRNA interaction network in HB remains elusive. Through a comparison between HB and normal liver samples in the GSE131329 dataset, we detected 580 upregulated differentially expressed mRNAs (DE-mRNAs) and 790 downregulated DE-mRNAs. As for the GSE153089 dataset, the first cluster of differentially expressed miRNAs (DE-miRNAs) were detected between fetal-type tumor and normal liver groups, while the second cluster of DE-miRNAs were detected between embryonal-type tumor and normal liver groups. Through the intersection of these two clusters of DE-miRNAs, 33 upregulated hub miRNAs, and 12 downregulated hub miRNAs were obtained. Based on the respective hub miRNAs, the upstream transcription factors (TFs) were detected via TransmiR v2.0, while the downstream target genes were predicted via miRNet database. The intersection of target genes of respective hub miRNAs and corresponding DE-mRNAs contributed to 250 downregulated candidate genes and 202 upregulated candidate genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated the upregulated candidate genes mainly enriched in the terms and pathways relating to the cell cycle. We constructed protein-protein interaction (PPI) network, and obtained 211 node pairs for the downregulated candidate genes and 157 node pairs for the upregulated candidate genes. Cytoscape software was applied for visualizing the PPI network and respective top 10 hub genes were identified using CytoHubba. The expression values of hub genes in the PPI network were subsequently validated through Oncopression database followed by quantitative real-time polymerase chain reaction (qRT-PCR) in HB and matched normal liver tissues, resulting in six significant downregulated genes and seven significant upregulated genes. The miRNA-mRNA interaction network was finally constructed. In conclusion, we uncover various miRNAs, TFs, and hub genes as potential regulators in HB pathogenesis. Additionally, the miRNA-mRNA interaction network, PPI modules, and pathways may provide potential biomarkers for future HB theranostics.
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Project description:Although the thin endometrium (TE) has been widely recognized as a critical factor in implantation failure, the contribution of miRNA-mRNA regulatory network to the development of disease etiology remains to be further elucidated. This study performed an integrative analysis of the miRNA-mRNA expression profiles in the thin and adjacent normal endometrium of eight patients with intrauterine adhesion to construct the transcriptomic regulatory networks. A total of 1,093 differentially expressed genes (DEGs) and 72 differentially expressed miRNAs (DEMs) were identified in the thin adhesive endometrium of the TE group compared with the control adjacent normal endometrial cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the DEGs and the target genes of DEM were significantly enriched in angiogenesis, cell growth regulation, and Wnt signaling pathway. Multiple hub genes (CAV1, MET, MAL2, has-mir-138, ARHGAP6, CLIC4, RRAS, AGFG1, has-mir-200, and has-mir-429) were identified by constructing the miRNA-mRNA regulatory networks. Furthermore, a miRNA-mRNA pathway function analysis was conducted, and the hub genes were enriched in the FoxO signaling pathway, cell growth regulation, inflammatory response regulation, and regulation of autophagy pathways. Our study is the first to perform integrated mRNA-seq and miRNA-seq analyses in the thin adhesive endometrium and the control adjacent normal endometrial cells. This study provides new insights into the molecular mechanisms underlying the formation of thin endometrium.
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Project description:BackgroundAccumulating evidence supports the importance of noncoding RNAs and exosomes in coronary heart disease (CHD). However, exosomal-associated competing endogenous RNA- (ceRNA-) mediated regulatory mechanisms in CHD are largely unexplored. The present study aimed to explore exosomal-associated ceRNA networks in CHD.MethodsData from 6 CHD patients and 32 normal controls were downloaded from the ExoRBase database. CHD and normal controls were compared by screening differentially expressed mRNAs (DEMs), lncRNAs (DELs), and circRNAs (DECs) in serum exosomes. MicroRNAs (miRNAs) targeting DEMs were predicted using the Targetscan and miRanda databases, and miRNAs targeted by DELs and DECs were predicted using the miRcode and starBase databases, respectively. The biological functions and related signaling pathways of DEMs were analyzed using the David and KOBAS databases. Subsequently, a protein-protein interaction (PPI) network was established to screen out on which hub genes enrichment analyses should be performed, and a ceRNA network (lncRNA/circRNA-miRNA-mRNA) was constructed to elucidate ceRNA axes in CHD.ResultsA total of 312 DEMs, 43 DELs, and 85 DECs were identified between CHD patients and normal controls. Functional enrichment analysis showed that DEMs were significantly enriched in "chromatin silencing at rDNA," "telomere organization," and "negative regulation of gene expression, epigenetic." PPI network analysis showed that 25 hub DEMs were closely related to CHD, of which ubiquitin C (UBC) was the most important. Hub genes were mainly enriched in "cellular protein metabolic process" functions. The exosomal-associated ceRNA regulatory network incorporated 48 DEMs, 73 predicted miRNAs, 10 DELs, and 15 DECs. The LncRNA/circRNA-miRNA-mRNA interaction axes (RPL7AP11/hsa-miR-17-5p/UBC and RPL7AP11/hsa-miR-20b-5p/UBC) were obtained from the network.ConclusionsOur findings provide a novel perspective on the potential role of exosomal-associated ceRNA network regulation of the pathogenesis of CHD.
| S-EPMC8249161 | biostudies-literature
Project description:BackgroundThe aim of this study was to explore the underlying molecular mechanism and potential molecular biomarkers of chronic pancreatitis (CP) and construct a miRNA-mRNA regulation network.MethodsTo explore the involvement of miRNAs in CP, we downloaded the miRNA and mRNA expression profiles of CP patients and healthy controls and identified the differentially expressed miRNAs and genes. Functional analysis was conducted and significant pathways were utilized. Finally, the miRNA-mRNA regulation network of CP was constructed.ResultsA total of 44 miRNA risk gene pathway relationships were identified, and a complex regulation network was constructed with 3 genes (ABL1, MYC, and ANAPC13) having the highest degree in affecting the network of CP. Importantly, 4 risk genes (NOTCH3, COX5A, THBS1, and KARS) and 1 risk miRNA (hsa-miR-324-5p) were identified with high prediction accuracy.ConclusionsIn conclusion, we analyzed miRNAs and mRNAs expression profiles in CP, 1 risk miRNA, and 4 risk genes were identified with high prediction accuracy as biomarkers of CP. Although further evaluation in clinical study is needed, our findings provide new insights into the pathogenesis of CP and may improve the diagnosis and therapy by identifying novel targets.
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Project description:BackgroundMicroRNAs are short RNA molecules that post-transcriptionally regulate gene expression. Today, microRNA target prediction remains challenging since very few have been experimentally validated and sequence-based predictions have large numbers of false positives. Furthermore, due to the different measuring rules used in each database of predicted interactions, the selection of the most reliable ones requires extensive knowledge about each algorithm.ResultsHere we propose two methods to measure the confidence of predicted interactions based on experimentally validated information. The output of the methods is a combined database where new scores and statistical confidences are re-assigned to each predicted interaction. The new scores allow the robust combination of several databases without the effect of low-performing algorithms dragging down good-performing ones. The combined databases obtained using both algorithms described in this paper outperform each of the existing predictive algorithms that were considered for the combination.ConclusionsOur approaches are a useful way to integrate predicted interactions from different databases. They reduce the selection of interactions to a unique database based on an intuitive score and allow comparing databases between them.
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Project description:BACKGROUND Nasopharyngeal carcinoma (NPC) is a common malignancy in South-East Asia. NPC is characterized by distant metastasis and poor prognosis. The pathophysiological mechanism of nasopharyngeal carcinoma is unknown. This study aimed to identify the crucial miRNAs in nasopharyngeal carcinoma and their target genes, and to discover the potential mechanism of nasopharyngeal carcinoma development. MATERIAL AND METHODS Microarray expression profiling of miRNA and mRNA from the Gene Expression Omnibus database was downloaded, and we performed a significance analysis of differential expression. An interaction network of miRNAs and target genes was constructed. The underlying function of differentially expressed genes was predicted through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. To validate the microarray analysis data, significantly different expression levels of miRNAs and target genes were validated by quantitative real-time polymerase chain reaction. RESULTS We identified 27 differentially expressed miRNAs and 982 differentially expressed mRNAs between NPC and normal control tissues. 12 miRNAs and 547 mRNAs were up-regulated and 15 miRNAs and 435 mRNAs were down-regulated in NPC samples. We found a total of 1185 negative correlation pairs between miRNA and mRNA. Differentially expressed target genes were significantly enriched in pathways in cancer, cell cycle, and cytokine-cytokine receptor interaction signaling pathways. Significantly differentially expressed miRNAs and genes, such as hsa-miR-205, hsa-miR-18b, hsa-miR-632, hsa-miR-130a, hsa-miR-34b, PIGR, SMPD3, CD22, DTX4, and CDC6, may play essential roles in the development of nasopharyngeal carcinoma. CONCLUSIONS hsa-miR-205, hsa-miR-18b, hsa-miR-632, hsa-miR-130a, and hsa-miR-34b may be related to the development of nasopharyngeal carcinoma by regulating the genes involved in pathways in cancer and cell cycle signaling pathways.
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Project description:Chronic obstructive pulmonary disease (COPD) is characterized by expiratory airflow limitation and symptoms such as shortness of breath. Although many studies have demonstrated dysregulated microRNA (miRNA) and gene (mRNA) expression in the pathogenesis of COPD, how miRNAs and mRNAs systematically interact and contribute to COPD development is still not clear. To gain a deeper understanding of the gene regulatory network underlying COPD pathogenesis, we used Sparse Multiple Canonical Correlation Network (SmCCNet) to integrate whole blood miRNA and RNA-sequencing data from 404 participants in the COPDGene study to identify novel miRNA-mRNA networks associated with COPD-related phenotypes including lung function and emphysema. We hypothesized that phenotype-directed interpretable miRNA-mRNA networks from SmCCNet would assist in the discovery of novel biomarkers that traditional single biomarker discovery methods (such as differential expression) might fail to discover. Additionally, we investigated whether adjusting -omics and clinical phenotypes data for covariates prior to integration would increase the statistical power for network identification. Our study demonstrated that partial covariate adjustment for age, sex, race, and CT scanner model (in the quantitative emphysema networks) improved network identification when compared with no covariate adjustment. However, further adjustment for current smoking status and relative white blood cell (WBC) proportions sometimes weakened the power for identifying lung function and emphysema networks, a phenomenon which may be due to the correlation of smoking status and WBC counts with the COPD-related phenotypes. With partial covariate adjustment, we found six miRNA-mRNA networks associated with COPD-related phenotypes. One network consists of 2 miRNAs and 28 mRNAs which had a 0.33 correlation (p = 5.40E-12) to forced expiratory volume in 1 s (FEV1) percent predicted. We also found a network of 5 miRNAs and 81 mRNAs that had a 0.45 correlation (p = 8.80E-22) to percent emphysema. The miRNA-mRNA networks associated with COPD traits provide a systems view of COPD pathogenesis and complements biomarker identification with individual miRNA or mRNA expression data.
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