Construction and analysis of miRNA-mRNA regulatory networks in the radioresistance of nasopharyngeal carcinoma.
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ABSTRACT:
SUBMITTER: Zhao H
PROVIDER: S-EPMC7648832 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMacrophage play a crucial role in regulating tumor progression. This study intended to investigate the circular RNA (circRNA) regulatory network associated with macrophage infiltration in hepatocellular carcinoma (HCC).MethodsThe immune cell fractions of HCC from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium were calculated by Estimation of the Proportion of Immune and Cancer cells algorithm. The differentially expressed mRNAs (DEmRNAs), microRNAs (DEmiRNAs) and circRNAs (DEcircRNAs) were identified from HCC and adjacent non-tumor cases of TCGA or Gene Expression Omnibus database. The DEmRNAs related to macrophage were selected by weighted gene co-expression network analysis and then utilized to generate the circRNA-miRNA-mRNA network. A hub circRNA regulatory network was established based on the co-expressed DEmiRNAs and DEmRNAs owning contrary correlation with the clinical characteristics, survival and macrophage infiltration level. A gene signature based on the DEmRNAs in hub network was also generated for further evaluation. The circRNA binding bite for miRNA was detected by luciferase assay.ResultsHigh macrophage fraction predicted good survival for HCC. A circRNA-miRNA-mRNA network was constructed by 27 macrophage related DEmRNAs, 21 DEmiRNAs, and 15 DEcircRNAs. Among this network, the expression of hsa-miR-139-5p was negatively correlated with CDCA8, KPNA2, PRC1 or TOP2A. Hsa-miR-139-5p low or targeted DEmRNA high expression was associated with low macrophage infiltration, high grade, advanced stage and poor prognosis of HCC. Additionally, the risk score generated by 4-DEmRNA signature could reflect the macrophage infiltration status and function as an independent prognostic factor for HCC. Finally, hsa_circ_0007456 acting on hsa-miR-139-5p related network was viewed as the hub circRNA regulatory network. Taken together, some circRNA regulatory networks may be associated with macrophage infiltration, which provides clues for mechanism study and therapeutic strategies of HCC.
| S-EPMC7583625 | biostudies-literature
Project description:Gelsemium elegans (Gardner & Champ.) Benth. (GE) has therapeutic effects for pain and malignant tumors but also has high toxicity. Its mechanism of toxicity has not yet been fully clarified, thus limiting its application. Meanwhile, evidence has shown that circRNAs are closely related to the progression of disease. However, very little is known about their expression profiles during intoxication. In this paper, circRNA/mRNA microarrays were respectively performed to detect their expression profiles in mice with acute GE intoxication versus normal controls. CircRNAs were verified by qRT-PCR in subsequent experiments. A regulation pattern of circRNA→miRNA→mRNA was deduced based on intersection analysis of circRNA/mRNA microarrays. The results revealed circRNAs (143) and mRNAs (1,921) were significantly expressed during intoxication. Most of the circRNAs were exonic, and most distributions in chromosomes were transcribed from chr1, chr2, chr7, and chr11. Furthermore, dysregulated expression of mmu-circRNA-013703 and mmu-circRNA-010022 was verified. Then a circRNA-targeted miRNA-mRNA co-expression network was constructed. The network map contained 2 circRNAs, 52 miRNAs, and 752 mRNAs. GO & KEGG analysis further predicted that mmu-circRNA-013703 and mmu-circRNA-010022 may participate in cellular survival/demise-related, neuron/synapse-related, and channel-related pathways. Based on functional modules analysis, a new network was formed, in which mmu-circRNA-013703 VS mmu-miR-361-3p linked to most mRNAs. Most of these mRNAs were known to be involved in the aforementioned functional module. This indicated that mmu-circRNA-013703 functioned as a sponge of miRNAs to regulate the more comprehensive circRNA-miRNA-mRNA co-expression network. Our approach revealed a landscape of dysregulated circRNA-miRNA-mRNA and may be valuable for the identification of new biomarkers during intoxication.
| S-EPMC6812611 | biostudies-literature
Project description:Radioresistance remains a challenge during nasopharyngeal carcinoma (NPC) radiotherapy. Numerous studies suggest that the miRNAs may play important roles in the regulation of radioresistance. miRNA-17-5p, which is located within the miR-17-92a cluster, could modulate tumor progression in different tissues by targeting multiple tumor associated genes. However, whether it is correlated with the radioresistance of tumor cells has not yet been elucidated. In our study, we have observed increasing miR-17-5p expression in radioresistant NPC tissues. The functional experiments suggested that miR-17-5p could clearly promote NPC cell proliferation and the cell cycle even after X-ray irradiation. Irradiation leads to tumor cell damage and death via ROS generation. The overexpression of miR-17-5p could protect NPC cells from apoptosis induced by irradiation. In addition, an in vivo experiment indicated that miR-17-5p promoted tumor growth with radiotherapy using the xenograft tumor model. A bioinformatics analysis and reporter assay were carried out to demonstrate that PTEN, which is a key regulator of AKT phosphorylation, is a target of miR-17-5p. The overexpression of miR-17-5p directly suppresses the mRNA and protein expression of PTEN. In addition, the rescue experiments showed that the AKT inhibitor can diminish the proliferation, promotion, and apoptosis inhibition effects on radioresistant NPC cells mediated by miR-17-5p. In conclusion, our findings demonstrated that miR-17-5p can enhance the radioresistance of NPC through the PTEN/AKT pathway, which is a biomarker of radioresistant NPC and a potential target for new therapeutic strategies.
| S-EPMC6944021 | biostudies-literature
Project description:PurposeNasopharyngeal carcinoma (NPC) is one of the most common malignant tumors of the head and neck. This study aimed to investigate the crucial genes and regulatory networks involved in the carcinogenesis of NPC using a bioinformatics approach.MethodsFive mRNA and two miRNA expression datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and miRNAs (DEMs) between NPC and normal samples were analyzed using R software. The WebGestalt tool was used for functional enrichment analysis, and protein-protein interaction (PPI) network analysis of DEGs was performed using STRING database. Transcription factors (TFs) were predicted using TRRUST and Transcriptional Regulatory Element Database (TRED). Kinases were identified using X2Kgui. The miRNAs of DEGs were predicted using miRWalk database. A kinase-TF-mRNA-miRNA integrated network was constructed, and hub nodes were selected. The hub genes were validated using NPC datasets from the GEO and Oncomine databases. Finally, candidate small-molecule agents were predicted using CMap.ResultsA total of 122 DEGs and 44 DEMs were identified. DEGs were associated with the immune response, leukocyte activation, endoplasmic reticulum stress in GO analysis, and the NF-κB signaling pathway in KEGG analysis. Four significant modules were identified using PPI network analysis. Subsequently, 26 TFs, 73 kinases, and 2499 miRNAs were predicted. The predicted miRNAs were cross-referenced with DEMs, and seven overlapping miRNAs were selected. In the kinase-TF-mRNA-miRNA integrated network, eight genes (PTGS2, FN1, MMP1, PLAU, MMP3, CD19, BMP2, and PIGR) were identified as hub genes. Hub genes were validated with consistent results, indicating the reliability of our findings. Finally, six candidate small-molecule agents (phenoxybenzamine, luteolin, thioguanosine, reserpine, blebbistatin, and camptothecin) were predicted.ConclusionWe identified DEGs and an NPC regulatory network involving kinases, TFs, mRNAs, and miRNAs, which might provide promising insight into the pathogenesis, treatment, and prognosis of NPC.
| S-EPMC8566004 | biostudies-literature
Project description:Purpose: MicroRNA (miRNA) binds to target mRNA and inhibit post-transcriptional gene expression. It plays an essential role in regulating gene expression, cell cycle, and biological development. This study aims to identify potential miRNA-mRNA regulatory networks that contribute to the pathogenesis of lung squamous cell carcinoma (LUSC). Patients and Methods: MiRNA microarray and RNA-Seq datasets were obtained from the gene expression omnibus (GEO) databases, the cancer genome atlas (TCGA), miRcancer, and dbDEMC. The GEO2R tool, "limma" and "DEseq" R packages were used to perform differential expression analysis. Gene enrichment analysis was conducted using the DAVID, DIANA, and Hiplot tools. The miRNA-mRNA regulatory networks were screened from the experimentally validated miRNA-target interactions databases (miRTarBase and TarBase). External validation was carried out in 30 pairs of LUSC tissues by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). Receiver operating characteristic curve (ROC) and decision curve analysis (DCA) were conducted to evaluate the diagnostic value. Clinical, survival and phenotypic analysis of miRNA-mRNA regulatory networks were further explored. Results: We screened 5 miRNA and 10 mRNA expression datasets from GEO and identified 7 DE-miRNAs and 270 DE-mRNAs. After databases screening and correlation analysis, four pairs of miRNA-mRNA regulatory networks were screened out. The miRNA-mRNA network of miR-205-5p (up) and PTPRM (down) was validated in 30 pairs of LUSC tissues. MiR-205-5p and PTPRM have good diagnostic efficacy and are expressed differently in different clinical features and are related to tumor immunity. Conclusion: The research identified a potential miRNA-mRNA regulatory network, providing a new way to explore the genesis and development of LUSC.
| S-EPMC9197544 | 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:Recent advances in sequencing technologies and the discovery of non-coding RNAs (ncRNAs) have provided new insights in the molecular pathogenesis of cancers. Several studies have implicated the role of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and recently discovered circular RNAs (circRNAs) in tumorigenesis and metastasis. Unlike linear RNAs, circRNAs are highly stable and closed-loop RNA molecules. It has been established that circRNAs regulate gene expression by controlling the functions of miRNAs and RNA-binding protein (RBP) or by translating into proteins. The circRNA-miRNA-mRNA regulatory axis is associated with human diseases, such as cancers, Alzheimer's disease, and diabetes. In this study, we explored the interaction among circRNAs, miRNAs, and their target genes in various cancers using state-of-the-art bioinformatics tools. We identified differentially expressed circRNAs, miRNAs, and mRNAs on multiple cancers from publicly available data. Furthermore, we identified many crucial drivers and tumor suppressor genes in the circRNA-miRNA-mRNA regulatory axis in various cancers. Together, this study data provide a deeper understanding of the circRNA-miRNA-mRNA regulatory mechanisms in cancers.
| S-EPMC8149909 | biostudies-literature
Project description:PURPOSE:Prostate cancer (PCa) causes a common male urinary system malignant tumour, and the molecular mechanisms of PCa are related to the abnormal regulation of various signalling pathways. An increasing number of studies have suggested that mRNAs, miRNAs, lncRNAs, and TFs could play important roles in various biological processes that are associated with cancer pathogenesis. This study aims to reveal functional genes and investigate the underlying molecular mechanisms of PCa with bioinformatics. METHODS:Original gene expression profiles were obtained from the GSE64318 and GSE46602 datasets in the Gene Expression Omnibus (GEO). We conducted differential screens of the expression of genes (DEGs) between two groups using the online tool GEO2R based on the R software limma package. Interactions between differentially expressed miRNAs, mRNAs and lncRNAs were predicted and merged with the target genes. Co-expression of miRNAs, lncRNAs and mRNAs was selected to construct mRNA-miRNA-lncRNA interaction networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for the DEGs. Protein-protein interaction (PPI) networks were constructed, and transcription factors were annotated. Expression of hub genes in the TCGA datasets was verified to improve the reliability of our analysis. RESULTS:The results demonstrate that 60 miRNAs, 1578 mRNAs and 61 lncRNAs were differentially expressed in PCa. The mRNA-miRNA-lncRNA networks were composed of 5 miRNA nodes, 13 lncRNA nodes, and 45 mRNA nodes. The DEGs were mainly enriched in the nuclei and cytoplasm and were involved in the regulation of transcription, related to sequence-specific DNA binding, and participated in the regulation of the PI3K-Akt signalling pathway. These pathways are related to cancer and focal adhesion signalling pathways. Furthermore, we found that 5 miRNAs, 6 lncRNAs, 6 mRNAs and 2 TFs play important regulatory roles in the interaction network. The expression levels of EGFR, VEGFA, PIK3R1, DLG4, TGFBR1 and KIT were significantly different between PCa and normal prostate tissue. CONCLUSION:Based on the current study, large-scale effects of interrelated mRNAs, miRNAs, lncRNAs, and TFs established a new prostate cancer network. In addition, we conducted functional module analysis within the network. In conclusion, this study provides new insight for exploration of the molecular mechanisms of PCa and valuable clues for further research into the process of tumourigenesis and its development in PCa.
| S-EPMC6107126 | biostudies-literature
Project description:Parkinson's disease (PD) is the second-most common neurodegenerative disease, and its pathophysiology is associated with alpha-synuclein accumulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. MicroRNAs are small non-coding RNAs that regulate gene expression, and many previous studies have described their dysregulation in plasma, CSF, and in the brain of patients with PD. In this study, we aimed to provide a regulatory network analysis on differentially expressed miRNAs in the brain of patients with PD. Based on our systematic review with a focus on the substantia nigra and the putamen, we found 99 differentially expressed miRNAs in brain samples from patients with PD, which regulate 135 target genes. Five genes associated with neuronal survival (BCL2, CCND1, FOXO3, MYC, and SIRT1) were modulated by dysregulated miRNAs found in the substantia nigra and the putamen of patients with PD. The functional enrichment analysis found FoxO and PI3K-AKT signaling as pathways related to PD. In conclusion, our comprehensive analysis of brain-related miRNA-mRNA regulatory networks in PD showed that mechanisms involving neuronal survival signaling, such as cell cycle control and regulation of autophagy/apoptosis, may be crucial for the neurodegeneration of PD, being a promising way for novel disease-modifying therapies.
| S-EPMC8228551 | biostudies-literature
Project description:BackgroundPediatric hepatocellular carcinoma (HCC) is a group of liver cancers whose mechanisms behind their pathogenesis and progression are poorly understood.AimWe aimed to identify alterations in the expression of miRNAs and their putative target mRNAs in not only tumor tissues of patients with pediatric HCC but also in corresponding non-tumorous background livers by using liver tissues without underlying liver disease as a control.Methods and resultsWe performed a small-scale miRNA and mRNA profiling of pediatric HCC (consisting of fibrolamellar carcinoma [FLC] and non-FLC HCC) and paired liver tissues to identify miRNAs whose expression levels differed significantly from control livers without underlying liver disease. ToppMiR was used to prioritize both miRNAs and their putative target mRNAs in a gene-annotation network, and the mRNA profile was used to refine the prioritization. Our analysis generated prioritized lists of miRNAs and mRNAs from the following three sets of analyses: (a) pediatric HCC versus control; (b) FLC versus control; and (c) corresponding non-tumorous background liver tissues from the same patients with pediatric HCC versus control. No liver disease liver tissues were used as the control group for all analyses. Many miRNAs whose expressions were deregulated in pediatric HCC were consistent with their roles in adult HCC and/or other non-hepatic cancers. Our gene ontology analysis of target mRNAs revealed enrichment of biological processes related to the sustenance and propagation of cancer and significant downregulation of metabolic processes.ConclusionOur pilot study indicates that alterations in miRNA-mRNA networks were detected in not only tumor tissues but also corresponding non-tumorous liver tissues from patients with pediatric HCC, suggesting multi-faceted roles of miRNAs in disease progression. Our results may lead to novel hypotheses for future large-scale studies.
| S-EPMC9875636 | biostudies-literature