Identifying miRNA-mRNA Integration Set Associated With Survival Time.
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ABSTRACT:
SUBMITTER: Kim Y
PROVIDER: S-EPMC8276759 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung adenocarcinoma is a multifactorial disease. MicroRNA (miRNA) expression profiles are extensively used for discovering potential theranostic biomarkers of lung cancer. This work proposes an optimized support vector regression (SVR) method called SVR-LUAD to simultaneously identify a set of miRNAs referred to the miRNA signature for estimating the survival time of lung adenocarcinoma patients using their miRNA expression profiles. SVR-LUAD uses an inheritable bi-objective combinatorial genetic algorithm to identify a small set of informative miRNAs cooperating with SVR by maximizing estimation accuracy. SVR-LUAD identified 18 out of 332 miRNAs using 10-fold cross-validation and achieved a correlation coefficient of 0.88 ± 0.01 and mean absolute error of 0.56 ± 0.03 year between real and estimated survival time. SVR-LUAD performs well compared to some well-recognized regression methods. The miRNA signature consists of the 18 miRNAs which strongly correlates with lung adenocarcinoma: hsa-let-7f-1, hsa-miR-16-1, hsa-miR-152, hsa-miR-217, hsa-miR-18a, hsa-miR-193b, hsa-miR-3136, hsa-let-7g, hsa-miR-155, hsa-miR-3199-1, hsa-miR-219-2, hsa-miR-1254, hsa-miR-1291, hsa-miR-192, hsa-miR-3653, hsa-miR-3934, hsa-miR-342, and hsa-miR-141. Gene ontology annotation and pathway analysis of the miRNA signature revealed its biological significance in cancer and cellular pathways. This miRNA signature could aid in the development of novel therapeutic approaches to the treatment of lung adenocarcinoma.
| S-EPMC5548864 | biostudies-literature
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.
| S-EPMC8581181 | biostudies-literature
Project description:Although various factors may contribute to its initiation and progression, the etiology and prognostic factors of endometrial carcinoma (EC) remains not fully understood. We sought to understand the role of changes in transcriptome during the progress of EC by exploring public datasets. The aberrant expression characteristics of EC based on RNA-Seq and miRNA-seq data from The Cancer Genome Atlas (TCGA) were analyzed. Kaplan-Meier analysis was performed to assess the relationship between differently expressed genes (DEGs) and patient survival. As a result, 320 out of 4,613 differently expressed mRNAs (DE mRNAs) and 68 out of 531 differently expressed miRNAs (DE miRNAs) with a significantly poorer survival were determined. We predicted eight paired DE miRNAs and DE mRNAs through TargetScan. Patients with three out of the eight paired low rate of miRNA/mRNA (miR-497/EMX1, miR-23c/DMBX1, and miR-670/KCNS1) expression had a significantly poorer survival. Furthermore, the simultaneous presence of these selected low miRNA/mRNA pairs occurred in most patients and resulted in a significantly poorer survival rate. Luciferase reporter assay identified that EMX1 was a direct target of miR-497. Both low expression of miR-497 and overexpression of EMX1 were significantly associated with more advanced clinicopathologic characteristics (stage, tumor status, grade, and histology) besides survival (all P values < 0.05). Multivariate analysis also demonstrated that miR-497 remained an independent prognostic variable for overall survival. In summary, we identified that a series of DE mRNAs and miRNAs, including eight paired DE miRNAs and mRNAs, were associated with survival in EC. Clinical evaluation of downregulated miR-497 and paired upregulated EMX1 confirmed the value of our prediction analysis. The simultaneous presence of low rate of these selected low miRNA/mRNA pairs (miR-497/EMX1, miR-23c/DMBX1, and miR-670/KCNS1) might have a better prediction value. Therefore, further studies are required to validate these findings.
| S-EPMC6710979 | biostudies-literature
Project description:BackgroundWith the continuous discovery of microRNA's (miRNA) association with a wide range of biological and cellular processes, expression profile-based functional characterization of such post-transcriptional regulation is crucial for revealing its significance behind particular phenotypes. Profound advancement in bioinformatics has been made to enable in depth investigation of miRNA's role in regulating cellular and molecular events, resulting in a huge quantity of software packages covering different aspects of miRNA functional analysis. Therefore, an all-in-one software solution is in demand for a comprehensive yet highly efficient workflow. Here we present RBiomirGS, an R package for a miRNA gene set (GS) analysis.MethodsThe package utilizes multiple databases for target mRNA mapping, estimates miRNA effect on the target mRNAs through miRNA expression profile and conducts a logistic regression-based GS enrichment. Additionally, human ortholog Entrez ID conversion functionality is included for target mRNAs.ResultsBy incorporating all the core steps into one package, RBiomirGS eliminates the need for switching between different software packages. The modular structure of RBiomirGS enables various access points to the analysis, with which users can choose the most relevant functionalities for their workflow.ConclusionsWith RBiomirGS, users are able to assess the functional significance of the miRNA expression profile under the corresponding experimental condition by minimal input and intervention. Accordingly, RBiomirGS encompasses an all-in-one solution for miRNA GS analysis. RBiomirGS is available on GitHub (http://github.com/jzhangc/RBiomirGS). More information including instruction and examples can be found on website (http://kenstoreylab.com/?page_id=2865).
| S-EPMC5768164 | biostudies-literature
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.
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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:MicroRNAs (miRNAs) are small non-coding RNAs that cause mRNA degradation and translational inhibition. They are important regulators of development and cellular homeostasis through their control of diverse processes. Recently, great efforts have been made to elucidate their regulatory mechanism, but the functions of most miRNAs and their precise regulatory mechanisms remain elusive. With more and more matched expression profiles of miRNAs and mRNAs having been made available, it is of great interest to utilize both expression profiles to discover the functional regulatory networks of miRNAs and their target mRNAs for potential biological processes that they may participate in.We present a probabilistic graphical model to discover functional miRNA regulatory modules at potential biological levels by integrating heterogeneous datasets, including expression profiles of miRNAs and mRNAs, with or without the prior target binding information. We applied this model to a mouse mammary dataset. It effectively captured several biological process specific modules involving miRNAs and their target mRNAs. Furthermore, without using prior target binding information, the identified miRNAs and mRNAs in each module show a large proportion of overlap with predicted miRNA target relationships, suggesting that expression profiles are crucial for both target identification and discovery of regulatory modules.
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Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and severe side effect of first-line chemotherapeutic agents. The association between circular RNAs (circRNAs) and CIPN remains unclear. In this study, CIPN models were constructed with Taxol, while 134 differentially expressed circRNAs, 353 differentially expressed long non-coding RNAs, and 86 differentially expressed messenger RNAs (mRNAs) were identified utilizing RNA sequencing. CircRNA-targeted microRNAs (miRNAs) were predicted using miRanda, and miRNA-targeted mRNAs were predicted using TargetScan and miRDB. The intersection of sequencing and mRNA prediction results was selected to establish the circRNA-miRNA-mRNA networks, which include 15 circRNAs, 18 miRNAs, and 11 mRNAs. Functional enrichment pathway analyses and immune infiltration analyses revealed that differentially expressed mRNAs were enriched in the immune system, especially in T cells, monocytes, and macrophages. Cdh1, Satb2, Fas, P2ry2, and Zfhx2 were further identified as hub genes and validated by RT-qPCR, correlating with macrophages, plasmacytoid dendritic cells, and central memory CD4 T cells in CIPN. Additionally, we predicted the associated diseases, 36 potential transcription factors (TFs), and 30 putative drugs for hub genes using the DisGeNET, TRRUST, and DGIdb databases, respectively. Our results indicated the crucial role of circRNAs, and the immune microenvironment played in CIPN, providing novel insights for further research.
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Project description:The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs and other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other's expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long-non-coding RNA-associated ceRNA networks. Here, we identify an extended ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of five hormone-dependent (HD) cancers, i.e., prostate, breast, colon, rectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across five HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene-associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding the shared molecular pathogenesis in a group of related diseases.
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Project description:Existing methods often fail to recognize the conversions for the biological roles of the pairs of genes and microRNAs (miRNAs) between the tumor and normal samples. We have developed a novel cluster scoring method to identify messenger RNA (mRNA) and miRNA interaction pairs and clusters while considering tumor and normal samples jointly. Our method has identified 54 significant clusters for 15 cancer types selected from The Cancer Genome Atlas project. We also determined the shared clusters across tumor types and/or subtypes. In addition, we compared gene and miRNA overlap between lists identified in our liver hepatocellular carcinoma (LIHC) study and regulatory relationships reported from human and rat nonalcoholic fatty liver disease studies (NAFLD). Finally, we analyzed biological functions for the single significant cluster in LIHC and uncovered a significantly enriched pathway (phospholipase D signaling pathway) with six genes represented in the cluster, symbols: DGKQ, LPAR2, PDGFRB, PIK3R3, PTGFR and RAPGEF3.
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