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Stempor, Przemyslaw A., Michael Cauchi, and Paul Wilson. "MMpred: functional miRNA – mRNA interaction analyses by miRNA expression prediction." BMC Genomics 13, no. 1 (2012): 620. http://dx.doi.org/10.1186/1471-2164-13-620.
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Plotnikova, O. M., and M. Y. Skoblov. "Efficiency of the miRNA–mRNA Interaction Prediction Programs." Molecular Biology 52, no. 3 (May 2018): 467–77. http://dx.doi.org/10.1134/s0026893318020103.
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Wang, Zixing, Wenlong Xu, Haifeng Zhu, and Yin Liu. "A Bayesian Framework to Improve MicroRNA Target Prediction by Incorporating External Information." Cancer Informatics 13s7 (January 2014): CIN.S16348. http://dx.doi.org/10.4137/cin.s16348.
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MicroRNAs (miRNAs) are small regulatory RNAs that play key gene-regulatory roles in diverse biological processes, particularly in cancer development. Therefore, inferring miRNA targets is an essential step to fully understanding the functional properties of miRNA actions in regulating tumorigenesis. Bayesian linear regression modeling has been proposed for identifying the interactions between miRNAs and mRNAs on the basis of the integrated sequence information and matched miRNA and mRNA expression data; however, this approach does not use the full spectrum of available features of putative miRNA targets. In this study, we integrated four important sequence and structural features of miRNA targeting with paired miRNA and mRNA expression data to improve miRNA-target prediction in a Bayesian framework. We have applied this approach to a gene-expression study of liver cancer patients and examined the posterior probability of each miRNA-mRNA interaction being functional in the development of liver cancer. Our method achieved better performance, in terms of the number of true targets identified, than did other methods.
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Fang, Yi, Xiaoyong Pan, and Hong-Bin Shen. "Recent Deep Learning Methodology Development for RNA–RNA Interaction Prediction." Symmetry 14, no. 7 (June 23, 2022): 1302. http://dx.doi.org/10.3390/sym14071302.
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Genetic regulation of organisms involves complicated RNA–RNA interactions (RRIs) among messenger RNA (mRNA), microRNA (miRNA), and long non-coding RNA (lncRNA). Detecting RRIs is beneficial for discovering biological mechanisms as well as designing new drugs. In recent years, with more and more experimentally verified RNA–RNA interactions being deposited into databases, statistical machine learning, especially recent deep-learning-based automatic algorithms, have been widely applied to RRI prediction with remarkable success. This paper first gives a brief introduction to the traditional machine learning methods applied on RRI prediction and benchmark databases for training the models, and then provides a recent methodology overview of deep learning models in the prediction of microRNA (miRNA)–mRNA interactions and long non-coding RNA (lncRNA)–miRNA interactions.
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Ragan, Chikako, Michael Zuker, and Mark A. Ragan. "Quantitative Prediction of miRNA-mRNA Interaction Based on Equilibrium Concentrations." PLoS Computational Biology 7, no. 2 (February 24, 2011): e1001090. http://dx.doi.org/10.1371/journal.pcbi.1001090.
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Kondybayeva, Аida, Aigul Akimniyazova, Saltanat Kamenova, Gulsum Duchshanova, Dana Aisina, Alla Goncharova, and Аnatoliy Ivashchenko. "Prediction of miRNA interaction with mRNA of stroke candidate genes." Neurological Sciences 41, no. 4 (November 30, 2019): 799–808. http://dx.doi.org/10.1007/s10072-019-04158-x.
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Li, Yameng, Yukun Xu, Yawei Hou, and Rui Li. "Construction and Bioinformatics Analysis of the miRNA-mRNA Regulatory Network in Diabetic Nephropathy." Journal of Healthcare Engineering 2021 (November 18, 2021): 1–11. http://dx.doi.org/10.1155/2021/8161701.
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Background. MicroRNA (miRNA) has been confirmed to be involved in the occurrence, development, and prevention of diabetic nephropathy (DN), but its mechanism of action is still unclear. Objective. With the help of the GEO database, bioinformatics methods are used to explore the miRNA-mRNA regulatory relationship pairs related to diabetic nephropathy and explain their potential mechanisms of action. Methods. The DN-related miRNA microarray dataset (GSE51674) and mRNA expression dataset (GSE30122) are downloaded through the GEO database, online analysis tool GEO2R is used for data differential expression analysis, TargetScan, miRTarBase, and miRDB databases are used to predict potential downstream target genes regulated by differentially expressed miRNAs, and intersection with differential genes is used to obtain candidate target genes. According to the regulatory relationship between miRNA and mRNA, the miRNA-mRNA relationship pair is clarified, and the miRNA-mRNA regulatory network is constructed using Cytoscape. DAVID is used to perform GO function enrichment analysis and KEGG pathway analysis of candidate target genes. By GeneMANIA prediction of miRNA target genes and coexpressed genes, the protein interaction network is constructed. Results and Conclusions. A total of 67 differentially expressed miRNAs were screened in the experiment, of which 42 were upregulated and 25 were downregulated; a total of 448 differentially expressed mRNAs were screened, of which 93 were upregulated and 355 were downregulated. Using TargetScan, miRTarBase, and miRDB databases to predict downstream targets of differentially expressed miRNAs, 2283 downstream target genes coexisting in 3 databases were predicted to intersect with differentially expressed mRNAs to obtain 96 candidate target genes. Finally, 44 miRNA-mRNA relationship pairs consisting of 12 differentially expressed miRNAs and 27 differentially expressed mRNAs were screened out; further analysis showed that miRNA regulatory network genes may participate in the occurrence and development of diabetic nephropathy through PI3K/Akt, ECM-receptor interaction pathway, and RAS signaling pathway.
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Sweef, Osama, Chengfeng Yang, and Zhishan Wang. "The Oncogenic and Tumor Suppressive Long Non-Coding RNA–microRNA–Messenger RNA Regulatory Axes Identified by Analyzing Multiple Platform Omics Data from Cr(VI)-Transformed Cells and Their Implications in Lung Cancer." Biomedicines 10, no. 10 (September 20, 2022): 2334. http://dx.doi.org/10.3390/biomedicines10102334.
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Chronic exposure to hexavalent chromium (Cr(VI)) causes lung cancer in humans, however, the underlying mechanism has not been well understood. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are commonly studied non-coding RNAs. miRNAs function mainly through interaction with the 3′-untranslated regions of messenger RNAs (mRNAs) to down-regulate gene expression. LncRNAs have been shown to function as competing endogenous RNAs (ceRNAs) to sponge miRNAs and regulate gene expression. It is now well accepted that lncRNAs and miRNAs could function as oncogenes or tumor suppressors. Dysregulations of lncRNAs and miRNAs have been shown to play important roles in cancer initiation, progression, and prognosis. To explore the mechanism of Cr(VI) lung carcinogenesis, we performed lncRNA, mRNA, and miRNA microarray analysis using total RNAs from our previously established chronic Cr(VI) exposure malignantly transformed and passage-matched control human bronchial epithelial BEAS-2B cells. Based on the differentially expressed lncRNAs, miRNAs, and mRNAs between the control (BEAS-2B-Control) and Cr(VI)-transformed (BEAS-Cr(VI)) cells and by using the lncRNA–miRNA interaction and miRNA target prediction algorithms, we identified three oncogenic (HOTAIRM1/miR-182-5p/ERO1A, GOLGA8B/miR-30d-5p/RUNX2, and PDCD6IPP2/miR-23a-3p/HOXA1) and three tumor suppressive (ANXA2P1/miR-20b-5p/FAM241A (C4orf32), MIR99AHG/miR-218-5p/GPM6A, and SH3RF3-AS1/miR-34a-5p/HECW2) lncRNA–miRNA–mRNA regulatory axes. Moreover, the relevance of these three oncogenic and three tumor suppressive lncRNA–miRNA–mRNA regulatory axes in lung cancer was explored by analyzing publicly available human lung cancer omics datasets. It was found that the identified three oncogenic lncRNA–miRNA–mRNA regulatory axes (HOTAIRM1/miR-182-5p/ERO1A, GOLGA8B/miR-30d-5p/RUNX2, and PDCD6IPP2/miR-23a-3p/HOXA1) and the three tumor suppressive lncRNA–miRNA–mRNA regulatory axes (ANXA2P1/miR-20b-5p/FAM241A (C4orf32), MIR99AHG/miR-218-5p/GPM6A, and SH3RF3-AS1/miR-34a-5p/HECW2) have significant diagnostic and prognosis prediction values in human lung cancer. In addition, our recent studies showed that Cr(VI)-transformed cells display cancer stem cell (CSC)-like properties. Further bioinformatics analysis identified the oncogenic lncRNA–miRNA–mRNA regulatory axes as the potential regulators of cancer stemness. In summary, our comprehensive analysis of multiple platform omics datasets obtained from Cr(VI)-transformed human bronchial epithelial cells identified several oncogenic and tumor suppressive lncRNA–miRNA–mRNA regulatory axes, which may play important roles in Cr(VI) carcinogenesis and lung cancer in general.
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Wei, Jiabo, Haihong Zhu, Qijun Zhang, and Qin Zhang. "Prediction of Functional Genes in Primary Varicose Great Saphenous Veins Using the lncRNA-miRNA-mRNA Network." Computational and Mathematical Methods in Medicine 2022 (September 8, 2022): 1–14. http://dx.doi.org/10.1155/2022/4722483.
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Background. Long noncoding RNAs (lncRNAs) have been widely suggested to bind with the microRNA (miRNA) sites and play roles of competing endogenous RNAs (ceRNAs), which can thus affect and regulate target gene and mRNA expression. Such lncRNA-related ceRNAs are identified to exert vital parts in vascular disease. Nonetheless, it remains unknown about how the lncRNA-miRNA-mRNA network functions in the varicose great saphenous veins. Methods. This study acquired the lncRNA and mRNA expression patterns from the GEO database and identifies the differentially expressed mRNAs and lncRNAs by adopting the R software “limma” package. Then, miRcode, miRDB, miRTarbase, and TargetScan were used to establish the miRNA-mRNA pairs and lncRNA-miRNA pairs. In addition, the lncRNA-miRNA-mRNA ceRNA network was constructed by using Cytoscape. Protein-protein interaction, Gene Ontology functional annotations, and Kyoto Encyclopedia of Genes and Genomes enrichment were carried out to examine the candidate hub genes, the functions of genes, and the corresponding pathways. Results. In line with the preset theory, we constructed ceRNA network comprising 12 lncRNAs, 38 miRNAs, and 149 mRNAs. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the PI3K/Akt signaling pathway played a vital part in the development of varicose great saphenous veins. AC114730, AC002127, and AC073342 were significant biomarkers. At the same time, we predicted the potential miRNA, which may exert a significant influence on the varicose great saphenous veins, namely, miR-17-5p, miR-129-5p, miR-1297, miR-20b-5p, and miR-33a-3p. Conclusion. By performing ceRNA network analysis, our study detects new lncRNAs, miRNAs, and mRNAs, which can be applied as underlying biomarkers of varicose great saphenous veins and as therapeutic targets for the treatment of varicose great saphenous veins.
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Chen, Jiajia, and Liangzhi Li. "Multiple Regression Analysis Reveals MicroRNA Regulatory Networks in Oryza sativa under Drought Stress." International Journal of Genomics 2018 (October 4, 2018): 1–12. http://dx.doi.org/10.1155/2018/9395261.
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Drought is a major abiotic stress that reduces rice development and yield. miRNAs (microRNAs) are known to mediate posttranscriptional regulation under drought stress. Although the importance of individual miRNAs has been established, the crosstalks between miRNAs and mRNAs remain unearthed. Here we performed microarray analysis of miRNAs and matched mRNA expression profiles of drought-treated rice cultivar Nipponbare. Drought-responsive miRNA-mRNA regulations were identified by a combination of a partial least square (PLS) regression approach and sequence-based target prediction. A drought-induced network with 13 miRNAs and 58 target mRNAs was constructed, and four miRNA coregulatory modules were revealed. Functional analysis suggested that drought-response miRNA targets are enriched in hormone signaling, lipid and carbohydrate metabolism, and antioxidant defense. 13 candidate miRNAs and target genes were validated by RT-qPCR, hierarchical clustering, and ROC analysis. Two target genes (DWARF-3 and P0651G05.2) of miRNA coregulatory modules were further verified by RLM-5′ RACE. Together, our integrative study of miRNA-mRNA interaction provided attractive candidates that will help elucidate the drought-response mechanisms in Oryza sativa.
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Yu, Liwei, Tengfei Yao, Zhoulei Jiang, and Tong Xu. "Integrated Analysis of miRNA-mRNA Regulatory Networks Associated with Osteonecrosis of the Femoral Head." Evidence-Based Complementary and Alternative Medicine 2021 (August 12, 2021): 1–11. http://dx.doi.org/10.1155/2021/8076598.
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Osteonecrosis of the femoral head (ONFH) accounts for as many as 18% of total hip arthroplasties. Knowledge of genetic changes and molecular abnormalities could help identify individuals considered to be at a higher risk of developing ONFH. In this study, we sought to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) associated with ONFH by integrated bioinformatics analyses as well as to construct the miRNA-mRNA regulatory network involving in the pathogenesis of ONFH. We performed differential expression analysis using a gene expression profile GSE123568 and a miRNA expression profile GSE89587 deposited in the Gene Expression Omnibus and identified 47 DEmiRs (24 upregulated miRNAs and 23 downregulated miRNAs) and 529 DEGs (218 upregulated genes and 311 downregulated genes). Gene Ontology enrichment analyses of DEGs suggested that DEGs were significantly enriched in neutrophil activation, cytosol, and ubiquitin-protein transferase activity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs revealed that DEGs were significantly enriched in transcriptional misregulation in cancer. DEGs-based miRNA-mRNA regulatory networks were obtained by searching miRNA-mRNA prediction databases, TargetScan, miTarBase, miRMap, miRDB, and miRanda databases. Then, overlapped miRNAs were selected between these putative miRNAs and DEmiRs between ONFH and non-ONFH, and pairs of the DEmiR-DEG regulatory network were finally depicted. There were 12 nodes and 64 interactions for upDEmiR-downDEG regulatory networks and 6 nodes and 16 interactions for downDEmiR-upDEG regulatory networks. Using the STRING database, we established a protein-protein interaction network based on the overlapped DEGs between ONFH and non-ONFH. C5AR1, CDC27, CDC34, KAT2B, CPPED1, TFDP1, and MX2 were identified as the hub genes. The present study characterizes the miRNA profile, gene profile, and miRNA-mRNA regulatory network in ONFH, which may contribute to the interpretation of the pathogenesis of ONFH and the identification of novel biomarkers and therapeutic targets for ONFH.
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Lang, Claudia, Sakuntala Karunairetnam, Kim R. Lo, Andrew V. Kralicek, Ross N. Crowhurst, Andrew Peter Gleave, Robin M. MacDiarmid, and John Ronald Ingram. "Common Variants of the Plant microRNA-168a Exhibit Differing Silencing Efficacy for Human Low-Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1)." MicroRNA 8, no. 2 (February 26, 2019): 166–70. http://dx.doi.org/10.2174/2211536608666181203103233.
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Background: The discovery that a plant microRNA (miRNAs) from rice (Oryza sativa miR168a) can modify post-transcriptional expression of the mammalian. Low-Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1) gene highlights the potential for cross-kingdom miRNAmRNA interactions. Objective: To investigate whether common variants of the conserved miR168a family have the capability for similar cross-kingdom regulatory functions, we selected sequences from three dietary plant sources: rice (Oryza sativa), tomato (Solanum lycopersicum), apple (Malus domestica) and compared their ability to regulate human LDLRAP1 expression. Methods: Target prediction software intaRNA and RNAhybrid were used to analyze and calculate the energy and alignment score between the miR168a variants and human LDLRAP1 mRNA. An in vitro cell-based Dual-Luciferase® Reporter Assay (pmirGLO, Promega), was then used to validate the miRNA-mRNA interaction experimentally. Results: Computational analyses revealed that a single nucleotide difference at position 14 (from the 5’ end of the miRNA) creates a G:U wobble in the miRNA-mRNA duplex formed by tomato and apple miR168a variants. This G:U wobble had only a small effect on the free energy score (-33.8–34.7 kcal/mol). However, despite reasonable hybridization energy scores (<-20 kcal/mol) for all miR168a variants, only the rice miR168a variant lacking a G:U wobble significantly reduced LDLRAP1 transcript expression by 25.8 + 7.3% (p<0.05), as measured by relative luciferase activity. Conclusion: In summary, single nucleotide differences at key positions can have a marked influence on regulatory function despite similar predicted energy scores and miRNA-mRNA duplex structures.
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Kumar, Satish, Joanne E. Curran, Erica DeLeon, Ana C. Leandro, Tom E. Howard, Donna M. Lehman, Sarah Williams-Blangero, David C. Glahn, and John Blangero. "Role of miRNA-mRNA Interaction in Neural Stem Cell Differentiation of Induced Pluripotent Stem Cells." International Journal of Molecular Sciences 21, no. 19 (September 23, 2020): 6980. http://dx.doi.org/10.3390/ijms21196980.
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miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10−15–1.44 × 10−4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease.
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Lopacinska-Jørgensen, Joanna, Douglas V. N. P. Oliveira, Guy Wayne Novotny, Claus K. Høgdall, and Estrid V. Høgdall. "Integrated microRNA and mRNA signatures associated with overall survival in epithelial ovarian cancer." PLOS ONE 16, no. 7 (July 28, 2021): e0255142. http://dx.doi.org/10.1371/journal.pone.0255142.
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Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsa-miR-126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsa-miR-506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Thus, the evaluation on independent cohorts will further evaluate the performance of such findings.
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Zhang, Zhang, Shen, and Sun. "Novel MicroRNA Biomarkers for Colorectal Cancer Early Diagnosis and 5-Fluorouracil Chemotherapy Resistance but Not Prognosis: A Study from Databases to AI-Assisted Verifications." Cancers 12, no. 2 (February 3, 2020): 341. http://dx.doi.org/10.3390/cancers12020341.
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Colorectal cancer (CRC) is one of the major causes of cancer death worldwide. In general, early diagnosis for CRC and individual therapy have led to better survival for the cancer patients. Accumulating studies concerning biomarkers have provided positive evidence to improve cancer early diagnosis and better therapy. It is, however, still necessary to further investigate the precise biomarkers for cancer early diagnosis and precision therapy and predicting prognosis. In this study, AI-assisted systems with bioinformatics algorithm integrated with microarray and RNA sequencing (RNA-seq) gene expression (GE) data has been approached to predict microRNA (miRNA) biomarkers for early diagnosis of CRC based on the miRNA-messenger RNA (mRNA) interaction network. The relationships between the predicted miRNA biomarkers and other biological components were further analyzed on biological networks. Bayesian meta-analysis of diagnostic test was utilized to verify the diagnostic value of the miRNA candidate biomarkers and the combined multiple biomarkers. Biological function analysis was performed to detect the relationship of candidate miRNA biomarkers and identified biomarkers in pathways. Text mining was used to analyze the relationships of predicted miRNAs and their target genes with 5-fluorouracil (5-FU). Survival analyses were conducted to evaluate the prognostic values of these miRNAs in CRC. According to the number of miRNAs single regulated mRNAs (NSR) and the number of their regulated transcription factor gene percentage (TFP) on the miRNA-mRNA network, there were 12 promising miRNA biomarkers were selected. There were five potential candidate miRNAs (miRNA-186-5p, miRNA-10b-5, miRNA-30e-5p, miRNA-21 and miRNA-30e) were confirmed as CRC diagnostic biomarkers, and two of them (miRNA-21 and miRNA-30e) were previously reported. Furthermore, the combinations of the five candidate miRNAs biomarkers showed better prediction accuracy for CRC early diagnosis than the single miRNA biomarkers. miRNA-10b-5p and miRNA-30e-5p were associated with the 5-FU therapy resistance by targeting the related genes. These miRNAs biomarkers were not statistically associated with CRC prognosis.
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Kasimanickam, Vanmathy, Nishant Kumar, and Ramanathan Kasimanickam. "Investigation of Sperm and Seminal Plasma Candidate MicroRNAs of Bulls with Differing Fertility and In Silico Prediction of miRNA-mRNA Interaction Network of Reproductive Function." Animals 12, no. 18 (September 9, 2022): 2360. http://dx.doi.org/10.3390/ani12182360.
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Recent advances in high-throughput in silico techniques portray experimental data as exemplified biological networks and help us understand the role of individual proteins, interactions, and their biological functions. The objective of this study was to identify differentially expressed (DE) sperm and seminal plasma microRNAs (miRNAs) in high- and low-fertile Holstein bulls (four bulls per group), integrate miRNAs to their target genes, and categorize the target genes based on biological process predictions. Out of 84 bovine-specific, prioritized miRNAs analyzed by RT-PCR, 30 were differentially expressed in high-fertile sperm and seminal plasma compared to low-fertile sperm and seminal plasma, respectively (p ≤ 0.05, fold regulation ≥ 5 magnitudes). The expression levels of DE-miRNAs in sperm and seminal plasma followed a similar pattern. Highly scored integrated genes of DE-miRNAs predicted various biological and molecular functions, cellular process, and pathways. Further, analysis of the categorized genes showed association with pathways regulating sperm structure and function, fertilization, and embryo and placental development. In conclusion, highly DE-miRNAs in bovine sperm and seminal plasma could be used as a tool for predicting reproductive functions. Since the identified miRNA-mRNA interactions were mostly based on predictions from public databases, the causal regulations of miRNA-mRNA and the underlying mechanisms require further functional characterization in future studies.
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Balakrishnan, Ilango, Xiaodong Yang, Beverly Torok-Storb, Jay Hesselberth, and Manoj Pillai. "High Throughput Sequencing Following Cross-Linked Immune Precipitation (HITS-CLIP) of Argonaute (AGO) Identifies Mir-193a as a Regulator of Jagged1 In Marrow Stromal Cells." Blood 116, no. 21 (November 19, 2010): 3847. http://dx.doi.org/10.1182/blood.v116.21.3847.3847.
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Abstract Abstract 3847 MicroRNAs (miRNAs) are small non-coding RNAs with important roles in the post-transcriptional regulation of up to 30% of all vertebrate genes. Traditional methods to determine miRNA-mRNA interactions have included transcriptional profiling of miRNAs, bio-informatic prediction of miRNA-mRNA binding, analysis of 3` untranslated region (3`UTR) binding of miRNAs and over-expression of miRNAs in relevant cell types. These studies however fall short of demonstrating direct interaction between a miRNA and its target mRNAs. We applied a recently described biochemical technique of high throughput sequencing following cross-linked immune precipitation (HITS-CLIP) to dissecting the miRNA-mRNA interactions in two functionally distinct human marrow stromal cell lines. HITS-CLIP relies on the ability of ultraviolet (UV) radiation to cross-link RNA to proteins they are bound to, followed by immune-precipitation of the RNA-protein complex to isolate the cross-linked RNA and sequencing by high throughput techniques. As miRNA-mRNA interactions occur in close proximity to the argonaute proteins (AGO), an anti-argonaute monoclonal antibody was used to isolate the Ago-miRNA-mRNA complexes. The two stromal cell lines analyzed by HITS-CLIP (designated HS5 and HS27a) were isolated from a normal marrow primary long term culture (LTC), immortalized and extensively characterized for both function and expression profiles (mRNA and miRNA). HS5 was found to secrete growth factors that stimulate proliferation and differentiation of hematopoietic progenitors (G-CSF, IL-6, IL-1α and IL1β), whereas HS27a expresses activities associated with the stem cell niche (CXCL12, Angiopoietin-1, Jag1 etc). In keeping with this, HS5 conditioned media stimulated proliferation and differentiation of isolated CD34+ cells whereas HS27a supported CD34+ cells in an undifferentiated state. Sequence reads from the HITS-CLIP analysis from each of the cell lines were aligned to the human genome using the UCSC genome browser to identify Ago-mRNA and Ago-miRNA binding sites in both the cell lines. Interestingly, corresponding datasets from HS5 and HS27a were similar for the majority of mRNAs and miRNAs, but distinct for those mRNAs (such as Jag1, CXCL12, IL6 and GCSF) and miRNAs (such as miR-886-3p, miR-221, miR-181a and miR-193a) known to be differentially expressed between the two cell lines. We then validated the use of the HITS-CLIP strategy in stromal cells by analyzing one such Ago-mRNA binding site for Jagged1 (Jag1). Jag1 is a ligand for Notch1 and is expressed in those cells that support the hematopoietic stem cell (HSC) niche. The Notch pathway is a highly conserved signaling system critical in regulating several tissue systems including hematopoietic cells. This binding site, 1749 bp downstream of the transcriptional start-site for Jag1 was significantly more enriched in HS5 compared to HS27a. The site was also a predicted binding site for miR-193a, a miRNA over-expressed in HS5 compared to HS27a cells. Over-expression of miR-193a in HS27a cells resulted in the down-regulation of Jag1 protein (as measured by Western blotting). To confirm the direct interaction between Jag1 and miR-193a, we cloned this purported binding site downstream of the luciferase gene and co-transfected the plasmid with miR-193a. Luciferase activity was down-regulated greater than 50% when compared to control transfections suggesting a direct effect of miR-193a on Jag1 transcript. In summary, our data suggest that HITS-CLIP methodology can be used to define in vivo spatial interactions between miRNA and mRNAs in the marrow microenvironment (ME). It can also be used to define miRNA-based regulation of specific genes such as Jag1, which are critical to defining functional niches in the ME. Disclosures: No relevant conflicts of interest to declare.
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Liu, Baosuo, Lize San, Huayang Guo, Kecheng Zhu, Nan Zhang, Jingwen Yang, Bo Liu, Jilun Hou, and Dianchang Zhang. "Transcriptomic Analysis Reveals Functional Interaction of mRNA-lncRNA-miRNA in Trachinotus ovatus Infected by Cryptocaryon irritans." International Journal of Molecular Sciences 24, no. 21 (November 1, 2023): 15886. http://dx.doi.org/10.3390/ijms242115886.
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The skin of Trachinotus ovatus is a crucial component of the mucosal immune system and serves as the primary site of infection by Cryptocaryon irritans. In order to investigate the significant role of skin in C. irritans infection, a comprehensive transcriptome analysis was conducted on skin tissues from the infection group, infection-adjacent group, and infection group compared with the infection-adjacent group (ATT_vs_PER, ADJ_vs_PER, ATT_vs_ADJ). This study identified differentially expressed long non-coding RNAs (DE lncRNAs), microRNAs (DE miRNAs), and differentially expressed genes (DEGs). The prediction of lncRNA target genes was accomplished by utilizing positional relationship (co-location) and expression correlation (co-expression) with protein-coding genes. Subsequently, functional enrichment analysis was conducted on the target genes of differentially expressed lncRNAs, revealing their involvement in signaling pathways such as tight junction, MAPK, and cell adhesion molecules. This study describes the regulatory network of lncRNA-miRNA-mRNA in T. ovatus skin tissue infected with C. irritans. Functional prediction analysis showed that differentially expressed lncRNA and miRNA may regulate the expression of immune genes such as interleukin-8 (il8) to resist the infection of C. irritans. Conducting additional research on these non-coding RNAs will facilitate a deeper understanding of their immune regulatory function in T. ovatus during C. irritans infection. The study of non-coding RNA in this study laid a foundation for revealing the molecular mechanism of the immune system of T. ovatus to respond to the infection of C. irritans. It provided a choice for the molecular breeding of Trachinotus ovatus against C. irritans.
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Meyer, Sara E., Andrew M. Rogers, Ashish Lal, Judy Lieberman, Bruce J. Aronow, Kakajan Komurov, and H. Leighton Grimes. "Unbiased Analyses of Signaling Through Leukemia Associated MicroRNA." Blood 118, no. 21 (November 18, 2011): 2373. http://dx.doi.org/10.1182/blood.v118.21.2373.2373.
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Abstract Abstract 2373 MicroRNA (miRNA or miR) expression profiling of primary human acute myelogenous leukemia (AML) biopsies and human AML cell lines has identified miRNA expression patterns associated with cytogenetic subtypes of AML. Elevated expression of miR-196b is associated with 11q23 translocations (MLL), whereas elevated expression of miR-126 is associated with AML1/CBFβ rearrangements in AML. Moreover, miR-196b blocks normal granulopoiesis and miR-126 inhibits erythropoiesis. To understand how these miRNAs function in normal and abnormal-malignant hematopoiesis, we sought to identify the target mRNAs they regulate. Currently miRNA target identification relies mostly on computational prediction algorithms with high error rates, or indirect methods such as microarray expression analyses of mRNAs altered upon overexpression or inhibition of the miRNA of interest. Here we applied a novel unbiased method to identify direct miR-196b and miR-126 target mRNAs by capture of miRNA-bound mRNA complexes from human fibroblasts and human AML cell lines. mRNAs that were bound to the miRNA of interest were applied to microarray analyses, and those that were present in at least 2-fold or greater quantities over those associated with a negative control C. elegans miRNA were identified as putative targets. We identified 651 potential mRNA targets of miR-196b and 402 potential targets of miR-126. We validated this technique in several ways. First, we showed that captured mRNAs were significantly enriched for miRNA seed sequences by comparison with computer algorithm predicted targets (244/651 for miR-196b and 42/402 for miR-126), and then remaining mRNA 3'UTR sequences were examined using miRNA binding site prediction software. We also confirmed the microarray findings by qRT-PCR analyses of the captured mRNAs from multiple independent experiments. Bioinformatic gene network analyses revealed that the 651 miR-196b targets were significantly enriched for participation in cell cycle checkpoint control, kinetochore/centromere interaction during mitosis, and apoptosis. Additionally, some of the miR-196b candidate targets are know to be deregulated in bone marrow failure (myelodysplastic syndrome or MDS, hemolytic anemia, and thrombocytopenia) or have roles in granulocyte activation. Bioinformatic network analyses of the 402 miR-126 targets revealed significant enrichment for genes involved in mitotic spindle assembly, kinetochore/mitotic spindle interaction during mitosis, Rho-mediated cytoskeletal dynamics, and DNA damage repair. 199 targets were found in common between miR-196b and miR-126. Notably, cell cycle (G2/M checkpoint, and negative cell cycle regulators) was one of the most significantly enriched biological processes in the 199 shared target genes (p<0.001). Moreover, some of the miR-196b/miR-126 common targets participate in translational control complexes dysregulated in bone marrow failure (MDS), as well as transcriptional circuits deregulated in abnormal myeloid differentiation. In sum, we optimized and implemented an innovative microRNA-mRNA target capture approach that resulted in identification of hundreds of previously unknown miRNA targets in human cells. These recent discoveries of putative miR-196b and miR-126 targets suggest novel mechanisms of miRNA gene regulation in normal and defective hematopoiesis and leukemogenesis. The identification of these miRNA targets may also help explain their distinct expression patterns in cytogenetic subtypes of AML. Disclosures: No relevant conflicts of interest to declare.
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Liu, Li yuan, Dan Jiang, Yuliang Qu, Hongxia Wang, Yanting Zhang, Shaoqi Yang, Xiaoliang Xie, Shan Wu, Haijin Zhou, and Guangxian Xu. "Potential and functional prediction of six circular RNAs as diagnostic markers for colorectal cancer." PeerJ 10 (May 19, 2022): e13420. http://dx.doi.org/10.7717/peerj.13420.
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Background Circular RNAs (circRNAs) have been discovered in colorectal cancer (CRC), but there are few reports on the expression distribution and functional mining analysis of circRNAs. Methods Differentially expressed circRNAs in CRC tissues and adjacent normal tissues were screened and identified by microarray and qRT-PCR. ROC curves of the six circRNAs were analyzed. A series of bioinformatics analyses on differentially expressed circRNAs were performed. Results A total of 207 up-regulated and 357 down-regulated circRNAs in CRC were screened, and three top up-regulated and down-regulated circRNAs were chosen to be verified in 33 pairs of CRCs by qRT-PCR. 6 circRNAs showed high diagnostic values (AUC = 0.6860, AUC = 0.8127, AUC = 0.7502, AUC = 0.9945, AUC = 0.9642, AUC = 0.9486 for hsa_circRNA_100833, hsa_circRNA_103828, hsa_circRNA_103831 and hsa_circRNA_103752, hsa_circRNA_071106, hsa_circRNA_102293). A circRNA-miRNA-mRNA regulatory network (cirReNET) including six candidate circRNAs, 19 miRNAs and 210 mRNA was constructed, and the functions of the cirReNET were predicted and displayed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on these mRNAs and protein-protein interaction (PPI) network of the hub genes acquired by string and CytoHubba. Conclusion A cirReNET containing potential diagnostic and predictive indicators of CRCs and several critical circRNA-miRNA-mRNA regulatory axes (cirReAXEs) in CRC were mined, and may provide a novel route to study the mechanism and clinical targets of CRC.
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Li, Xing, Yunli Han, Dejun Li, Hai Yuan, Shiqin Huang, Xiaolan Chen, and Yuanhan Qin. "Identification and Validation of a Dysregulated miRNA-Associated mRNA Network in Temporal Lobe Epilepsy." BioMed Research International 2021 (October 22, 2021): 1–12. http://dx.doi.org/10.1155/2021/4118216.
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Objectives. This study is aimed at exploring the relationships between miRNAs and mRNAs and to characterize their biological functions in temporal lobe epilepsy (TLE). Methods. Novel clinical significant miRNAs and target genes and their potential underlying mechanisms have been discovered and explored by mining miRNAs and mRNA expression data of TLE patients using various bioinformatics methods. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to validate the bioinformatic analysis results. Results. A total of 6 dysregulated miRNAs and 442 differentially expressed genes (DEGs) related to TLE were obtained from GEO database (GSE114701 and GSE127871 datasets). A protein-protein interaction (PPI) network containing the 442 DEGs was established. mRNA response elements from the 6 dysregulated miRNAs were predicted using the miRDB and TargetScan bioinformatic tools. By merging the identified targets of the dysregulated miRNAs and the 247 downregulated DEGs, a miRNA-mRNA network was constructed revealing the interaction of miR-484 with eight mRNAs (ABLIM2, CEP170B, CTD-3193O13.9, EFNA5, GAP43, PRKCB, FXYD7, and NCAN). A weighted correlation network analysis (WGCNA) based on the eight genes was established and demonstrated that these mRNAs, except FXYD7 and NCAN, were hub genes in the network. Gene Oncology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the six hub genes were mainly involved in cellular-related biological functions and the neurotransmitter synapse pathway. The differences in expression levels of the miR-484 and the three hub genes (CTD-3193O13.9, EFNA5, and PRKCB) observed experimentally in TLE patients compared to those of healthy controls were consistent with the WGCNA prediction. Conclusion. Our study suggests that understanding the miRNA-mRNA interactions will provide insights into the epilepsy pathogenesis. In addition, our results indicate that miR-484 may be a promising novel biomarker for TLE.
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Guo, Xu, Sui Chen, Sihan Wang, Hao Zhang, Fanxing Yin, Panpan Guo, Xiaoxu Zhang, Xuesong Liu, and Yanshuo Han. "CircRNA-Based Cervical Cancer Prognosis Model, Immunological Validation and Drug Prediction." Current Oncology 29, no. 11 (October 25, 2022): 7994–8018. http://dx.doi.org/10.3390/curroncol29110633.
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Background: Cervical cancer (CC) is a common cancer in female, which is associated with problems like poor prognosis. Circular RNA (circRNA) is a kind of competing endogenous RNA (ceRNA) that has an important role in regulating microRNA (miRNA) in many cancers. The regulatory mechanisms of CC immune microenvironment and the transcriptome level remain to be fully explored. Methods: In this study, we constructed the ceRNA network through the interaction data and expression matrix of circRNA, miRNA and mRNA. Meanwhile, based on the gene expression matrix, CIBERSORT algorithm was used to reveal contents of tumor-infiltrating immune cells (TIICs). Then, we screened prognostic markers based on ceRNA network and immune infiltration and constructed two nomograms. In order to find immunological differences between the high- and low-risk CC samples, we examined multiple immune checkpoints and predicted the effect of PD-L1 ICI immunotherapy. In addition, the sensitive therapeutics for high-risk patients were screened, and the potential agents with anti-CC activity were predicted by Connective Map (CMap). Results: We mapped a ceRNA network including 5 circRNAs, 17 miRNAs and 129 mRNAs. From the mRNA nodes of the network six genes and two kind of cells were identified as prognostic makers for CC. Among them, there was a significant positive correlation between CD8+ T cells and SNX10 gene. The results of TIDE and single sample GSEA (ssGSEA) showed that T cells CD8 do play a key role in inhibiting tumor progression. Further, our study screened 24 drugs that were more sensitive to high-risk CC patients and several potential therapeutic agents for reference. Conclusions: Our study identified several circRNA-miRNA-mRNA regulatory axes and six prognostic genes based on the ceRNA network. In addition, through TIIC, survival analysis and a series of immunological analyses, T cells were proved to be good prognostic markers, besides play an important role in the immune process. Finally, we screened 24 potentially more effective drugs and multiple potential drug compounds for high- and low-risk patients.
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Zhang, Jian, Jiying Wang, Cai Ma, Wenlei Wang, Heng Wang, and Yunliang Jiang. "Comparative Transcriptomic Analysis of mRNAs, miRNAs and lncRNAs in the Longissimus dorsi Muscles between Fat-Type and Lean-Type Pigs." Biomolecules 12, no. 9 (September 13, 2022): 1294. http://dx.doi.org/10.3390/biom12091294.
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In pigs, meat quality and production are two important traits affecting the pig industry and human health. Compared to lean-type pigs, fat-type pigs contain higher intramuscular fat (IMF) contents, better taste and nutritional value. To uncover genetic factors controlling differences related to IMF in pig muscle, we performed RNA-seq analysis on the transcriptomes of the longissimus dorsi (LD) muscle of Laiwu pigs (LW, fat-type pigs) and commercial Duroc × Landrace × Yorkshire pigs (DLY, lean-type pigs) at 150 d to compare the expression profiles of mRNA, miRNA and lncRNA. A total of 225 mRNAs, 12 miRNAs and 57 lncRNAs were found to be differentially expressed at the criteria of |log2(foldchange)| > 1 and q < 0.05. The mRNA expression of LDHB was significantly higher in the LD muscle of LW compared to DLY pigs with log2(foldchange) being 9.66. Using protein interaction prediction method, we identified more interactions of estrogen-related receptor alpha (ESRRA) associated with upregulated mRNAs, whereas versican (VCAN) and proenkephalin (PENK) were associated with downregulated mRNAs in LW pigs. Integrated analysis on differentially expressed (DE) mRNAs and miRNAs in the LD muscle between LW and DLY pigs revealed two network modules: between five upregulated mRNA genes (GALNT15, FKBP5, PPARGC1A, LOC110258214 and LOC110258215) and six downregulated miRNA genes (ssc-let-7a, ssc-miR190-3p, ssc-miR356-5p, ssc-miR573-5p, ssc-miR204-5p and ssc-miR-10383), and between three downregulated DE mRNA genes (IFRD1, LOC110258600 and LOC102158401) and six upregulated DE miRNA genes (ssc-miR1379-3p, ssc-miR1379-5p, ssc-miR397-5p, ssc-miR1358-5p, ssc-miR299-5p and ssc-miR1156-5p) in LW pigs. Based on the mRNA and ncRNA binding site targeting database, we constructed a regulatory network with miRNA as the center and mRNA and lncRNA as the target genes, including GALNT15/ssc-let-7a/LOC100523888, IFRD1/ssc-miR1379-5p/CD99, etc., forming a ceRNA network in the LD muscles that are differentially expressed between LW and DLY pigs. Collectively, these data may provide resources for further investigation of molecular mechanisms underlying differences in meat traits between lean- and fat-type pigs.
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Wei, Lin, Xia Li, Lijuan Wang, Yanyan Song, and Hongmei Dong. "Comprehensive Analysis of RNA Expression Profile Identifies Hub miRNA-circRNA Interaction Networks in the Hypoxic Ischemic Encephalopathy." Computational and Mathematical Methods in Medicine 2021 (September 21, 2021): 1–18. http://dx.doi.org/10.1155/2021/6015473.
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Hypoxic ischemic encephalopathy (HIE) is classified as a sort of serious nervous system syndrome that occurs in the early life period. Noncoding RNAs had been confirmed to have crucial roles in human diseases. So far, there were few systematical and comprehensive studies towards the expression profile of RNAs in the brain after hypoxia ischemia. In this study, 31 differentially expressed microRNAs (miRNAs) with upregulation were identified. In addition, 5512 differentially expressed mRNAs, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) were identified in HIE groups. Bioinformatics analysis showed these circRNAs and mRNAs were significantly enriched in regulation of leukocyte activation, response to virus, and neutrophil degranulation. Pathway and its related gene network analysis indicated that HLA − DPA1, HLA − DQA2, HLA − DQB1, and HLA − DRB4 have a more crucial role in HIE. Finally, miRNA-circRNA-mRNA interaction network analysis was also performed to identify hub miRNAs and circRNAs. We found that miR-592 potentially targeting 5 circRNAs, thus affecting 15 mRNA expressions in HIR. hsa_circ_0068397 and hsa_circ_0045698 were identified as hub circRNAs in HIE. Collectively, using RNA-seq, bioinformatics analysis, and circRNA/miRNA interaction prediction, we systematically investigated the differentially expressed RNAs in HIE, which could give a new hint of understanding the pathogenesis of HIE.
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Han, Yifan, and Lei Zhou. "MiRNA-4665-3p Regulates Expression of PLD5 in Thyroid Cancer Patients and Predicts Death." Journal of Biomaterials and Tissue Engineering 9, no. 7 (July 1, 2019): 871–80. http://dx.doi.org/10.1166/jbt.2019.2068.
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Thyroid cancer has become an increasingly common malignant tumor around the world, and its incidence is increasing year by year. In this study, mRNA microarray data of thyroid cancer patients from four periods were collected from the TCGA database. We performed a series of bioinformatics analyses on these mRNA expression profiles, including differential analysis, co-expression analysis, enrichment analysis, regulator prediction, and survival analysis. There were 13126, 10914, 13585, and 13241 differential genes in the four periods; 4822 differential genes were obtained by union and deduplication (p < 0.01). Weighted gene co-expression network analysis indicated a total of 21 functional disorder modules. In each module, PLD5, CHD4, ADGRA3, ITGA3, etc. were the key genes. Enrichment analysis showed that the dysfunctional module genes were mainly related to pre-replicative complex assembly, Cytokine–cytokine receptor interaction, and MAPK signaling pathway. We downloaded thyroid cancer-associated miRNA microarray data from the GEO database for differential analysis. Then, we crossed the predicted ncRNA with the differential miRNA to obtain thyroid cancer-associated regulatory factors. Finally, we found that miRNA-4665-3p regulates the core gene PLD5, and six regulators such as miRNA-3140-3p and miRNA-324-3p regulate the core gene CHD4. Survival analysis showed that both up-regulation of PLD5 expression and down-regulation of CHD4 expression accelerated patient death. According to the above analysis, we believe miRNA-4665-3p regulates the expression of PLD5 and affects the development of thyroid cancer. Its up-regulation promotes the death of patients.
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Zhang, Chengyao, Wei Cao, Jiawu Wang, Jiannan Liu, Jialiang Liu, Hao Wu, Siyi Li, and Chenping Zhang. "A prognostic long non-coding RNA-associated competing endogenous RNA network in head and neck squamous cell carcinoma." PeerJ 8 (September 15, 2020): e9701. http://dx.doi.org/10.7717/peerj.9701.
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Background This study aimed to develop multi-RNA-based models using a competing endogenous RNA (ceRNA) regulatory network to provide survival risk prediction in head and neck squamous cell carcinoma (HNSCC). Methods All long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA expression data and clinicopathological features related to HNSCC were derived from The Cancer Genome Atlas. Differentially expressed RNAs were calculated using R. Prognostic factors were identified using univariate Cox regression analysis. Functional analysis was performed using GO, KEGG pathways, and PPI network. Based on the results, we derived a risk signature and compared high- and low-risk subgroups using LASSO regression analysis. Survival analysis and the relationship between risk signature and clinicopathological features were performed using log-rank tests and Cox regression analysis. A ceRNA regulatory network was constructed, and prognostic lncRNAs and miRNA expression levels were validated in vitro and in vivo. Results A list of 207 lncRNAs, 18 miRNAs and 362 mRNAs related to overall survival was established. Five lncRNAs (HOTTIP, LINC00460, RMST, SFTA1P, and TM4SF19-AS1), one miRNA (hsa-miR-206), and one mRNA (STC2) were used to construct the ceRNA network. Three prognostic models contained 13 lncRNAs, eight miRNAs, and 17 mRNAs, which correlated with the patient status, disease-free survival (DFS), stage, grade, T stage, N stage, TP53 mutation status, angiolymphatic invasion, HPV status, and extracapsular spread. KEGG pathway analysis revealed significant enrichment of “Transcriptional misregulation in cancer” and “Neuroactive ligand-receptor interaction.” In addition, HOTTIP, LINC00460, miR-206 and STC2 were validated in GTEx data, GEO microarrays and six HNSCC cell lines. Conclusions Our findings clarify the interaction of ceRNA regulatory networks and crucial clinicopathological features. These results show that prognostic biomarkers can be identified by constructing multi-RNA-based prognostic models, which can be used for survival risk prediction in patients with HNSCC.
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Pallasch, Christian P., Susanne Hagist, Michaela Patz, Alexandra Schulz, Svenja Debey, Daniela Eggle, Joachim L. Schultze, Michael Hallek, and Clemens-Martin Wendtner. "Deregulation of Micrornas Results in Overexpression of Oncogenic Transcription Factors Involved in Pathogenesis of CLL." Blood 112, no. 11 (November 16, 2008): 2075. http://dx.doi.org/10.1182/blood.v112.11.2075.2075.
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Abstract MicroRNAs play a key role in the control of translation and mRNA degradation by binding to the 3′ untranslated regions of mRNAs. Immune cell development is especially dependent on miRNA regulation like miR-155 in germinal center development. Distinct miRNA-deregulation has been recently identified in CLL, however the proposed model of miR-15/16 mediated pathogenesis remains controversial. CLL cells of 50 treatment-naïve patients and peripheral B-cells of 14 healthy donors were separated by untouched depletion and processed for isolation of at least 200 ng total RNA. A new Illumina based Bead Chip was applied using 100 ng of total RNA for reliable hybridization. Target prediction of deregulated miRNAs was performed by in-silico predictions of miRNA-target gene interactions by TargetScan and PicTar. MiRNA target candidates were analyzed for differential protein expression in healthy donor B cells versus CLL cells. The applied technology was repetitively controlled and demonstrated to reveal reliable quantitative results. Comparing CLL samples with healthy donor B cells an overall decrease of miRNAs was observed in CLL samples. In total 19 miRNA were identified to be significantly lower expressed in CLL. 7 miRNAs were overexpressed in CLL. Comparing previously published data we could reliably identify upregulation of miR- 155 and downreguation of miR-181. However, the intensively discussed deregulation of miR-15 and miR-16 could not be verified. Furthermore we identified a so far not described CLL-specific miRNA-fingerprint of 26 miRNAs. Based on this fingerprint we analyzed for miRNA targets based on target prediction. A significantly focused number of transcription factors were identified by this primary screen. We could confirm predicted over-expression of oncogenic transcription factors by immunoblotting analysis. Targeting of deregulated miRNAs to 3′UTR of target genes was assessed by luciferase reporter assays. Decreased activity of 3’UTR-reporter construct was achieved by cotransfection with synthetic miRNAs together with target 3′UTRs. Targeted mutation of putative binding sites revealed an abrogation of miRNA-mediated suppression of luciferase activity confirming specificity of miRNA-3′UTR interaction of target genes. Here we could identify significant down-regulation of miRNA in CLL, a so far not identified cluster of deregulated miRNAs led to the identification of oncogenic transcription factors as novel target genes and pathogenic pathways in CLL. A key question remains regarding the cause of down-regulation of miRNAs mainly observed in CLL. Since no genomic hotspot is apparent, an impaired processing of pre-/pri-miRNAs or suppressive transcription factor loops have to be hypothesized and investigated to reveal the regulatory role of miRNA in malignant transformation of CLL.
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Balakrishnan, Ilango, Xiaodong Yang, Beverly Torok-Storb, Jay Hesselberth, and Manoj M. Pillai. "High Throughput Sequencing Following Cross-Linked Immune Precipitation (HITS-CLIP) of Argonaute (AGO) Identifies Mir-9 As a Regulator of MMP2 in the Marrow Microenvironment (ME)." Blood 118, no. 21 (November 18, 2011): 2392. http://dx.doi.org/10.1182/blood.v118.21.2392.2392.
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Abstract Abstract 2392 There is increasing recognition of the role of small noncoding RNAs in post-transcriptional regulation of gene expression in diverse tissues of eukaryotic organisms including vertebrates. MicroRNAs (miRNAs) are the best studied amongst these small RNAs and are thought to act by binding to the 3' untranslated regions (3' UTRs) of mature mRNAs in a sequence-specific fashion and preventing the initiation of peptide translation and/ or initiating mRNA degradation. Recent evidence suggests that miRNA-based regulation might involve binding to regions other than 3' UTRs including coding regions. Current approaches to defining miRNA-mRNA interactions are mostly restricted to those based on bio-informatic prediction, protein down-regulation following in-vitro transfection of miRNA precursors and luciferase assays to determine binding to 3' UTRs. None of these methods however show direct interaction between a specific miRNA and its purported target RNA. Bio-informatics-based approaches are also prone to false positive and negative results given the short length of sequence matching, and reliance on heuristics and cross-species conservation. Newer genome-wide approaches like HITS-CLIP (High Throughput Sequencing following Cross Linked Immuno Precipitation, or CLIP-Seq) overcome some of these limitations by directly isolating the miRNA-mRNA interactome bound to argonaute (AGO), a critical component of the rna-induced silencing complex (RISC)1. HITS-CLIP utilizes the ability of ultraviolet (UV) light to cross-link RNAs to proteins in their close proximity. The crosslinked miRNA-mRNA-Ago complexes are then isolated and the RNA reverse transcribed to cDNA libraries and sequenced by next generation sequencing (NGS). Given the widespread role of miRNAs in several vertebrate tissues, we hypothesized that miRNA-regulation of gene expression is operant in the hematopoietic microenvironment (ME) and thus contributes to regulation of hematopoiesis. We hence used HITS-CLIP to analyze the miRNA-mRNA interactome of three key cellular components of the ME: stromal cells, endothelium and macrophages. We have previously reported on the use of the stromal cell lines Hs27a and Hs5 to define specific functional niches within the ME. Hs27a can functionally support primitive hematopoietic stem and progenitor cells (HSPC) in cobblestone areas (CSAs) and express high levels of factors known to support HSPC such as SDF1, Jagged1 and Angiopoietin1. In contrast, Hs5 drives HSPC to mature lineages and secretes high levels of cytokines like IL1, IL6 and GCSF. Human umbilical vein endothelial cells (HUVECs) and MCSF-treated CD14+ cells were utilized for the endothelial and macrophage cultures respectively. The HITS-CLIP datasets from each of these populations were enriched for a putative binding site for miR-9 in the coding region of Matrix Metalloproteinase 2 (MMP2) mRNA. MMP2 belongs to a family of endopeptidases critical in the remodeling of extracellular matrix in several tissues and in the egress/ homing of HSPC to their functional niches in the ME. Functional binding of miR-9 to MMP2 was validated by Western-blotting of stromal cells transfected with miR-9 which revealed > 50% reduction of protein levels when compared to control-transfected cells. This was also confirmed by gelatin zymography which showed significantly reduced MMP2 activity in stromal cells transfected with miR-9. Finally, to confirm direct binding of miR-9 to the putative binding region on the MMP2 transcript, we cloned this microRNA responsive region (MRE) downstream of the Renilla luciferase gene and assayed its activity by luciferase assays. MiR-9 transfection down-regulated luciferase activity > 50% confirming direct binding to the MRE. Our results show that genome-wide approaches such as HITS-CLIP can be used to define in vivo miRNA-mRNA interactions in the ME and should be considered in studies that define such interactions given the significant false-positive and false negative results associated with approaches based on bio-informatics alone. The approach can also define specific interactions between miRNAs and mRNAs such as MMP2, of relevance to regulation of the hematopoietic ME. Disclosures: No relevant conflicts of interest to declare.
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Wang, Haiming, Yue Hu, Yujie Xie, Li Wang, Jianxiong Wang, Lei Lei, Maomao Huang, and Chi Zhang. "Prediction of MicroRNA and Gene Target in Synovium-Associated Pain of Knee Osteoarthritis Based on Canonical Correlation Analysis." BioMed Research International 2019 (October 13, 2019): 1–9. http://dx.doi.org/10.1155/2019/4506876.
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Inflammation plays a central role in knee osteoarthritis (OA) pathogenesis (C. R. Scanzello, 2017). The synovial membrane inflammation is associated with disease progression and represents a primary source of agony in knee OA (L. A. Stoppiello et al., 2014). Many inflammatory mediators may have biomarker utility. To identify synovium related to knee OA pain biomarkers, we used canonical correlation analysis to analyze the miRNA-mRNA dual expression profiling data and extracted the miRNAs and mRNAs. After identifying miRNAs and mRNAs, we built an interaction network by integrating miRWalk2.0. Then, we extended the network by increasing miRNA-mRNA pairs and identified five miRNAs and four genes (TGFBR2, DST, TBXAS1, and FHLI) through the Spearman rank correlation test. For miRNAs involved in the network, we further performed the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses, whereafter only those mRNAs overlapped with the Online Mendelian Inheritance in Man (OMIM) genetic database were analyzed. Receiver operating characteristic (ROC) curve and support vector machine (SVM) classification were taken into the analysis. The results demonstrated that all the recognized miRNAs and their gene targets in the network might be potential biomarkers for synovial-associated pain in knee OA. This study predicts the underlying risk biomarkers of synovium pain in knee OA.
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Huang, Junshen, Yuxi Li, Ziwei Ye, Ziying Cheng, Jiajun Huang, Shixin Lu, Kaihui Su, Yuwei Liang, Ming Li, and Lin Huang. "Prediction of a Potential Mechanism of Intervertebral Disc Degeneration Based on a Novel Competitive Endogenous RNA Network." BioMed Research International 2021 (June 30, 2021): 1–15. http://dx.doi.org/10.1155/2021/6618834.
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Low back pain which resulted from intervertebral disc degeneration (IDD) is a common health problem that afflicts people all over the world. Due to the lack of an overall understanding of the molecular interactions involved in IDD, we hope to better understand the pathogenetic mechanisms that drive the degenerative process. The purpose of this study is to obtain mRNAs, miRNAs, lncRNAs, and circRNAs associated with IDD gained from public databases and to establish an interaction network. According to the results of microarray analysis and bioinformatics analysis from the contrast of IDD and normal nucleus pulposus tissues, a total of 49 mRNAs, 10 miRNAs, 30 lncRNAs, and 4 circRNAs were obtained and a lncRNA/circRNA–miRNA–mRNA interaction network was constructed. NEAT1–miR-5100–COL10A1 and miR663AHG/HEIH/hsa-circ-0003600–miR-4741–HAS2/HYAL1/LYVE1 might be potential interaction axes of the molecular mechanism in IDD. The increased expression of NEAT1 might inhibit miR-5100 and subsequently upregulate the expression of COL10A1, which leads to IDD, while the increased expression of miR663AHG/HEIH/hsa-circ-0003600 might inhibit miR-4741 and indirectly upregulate HAS2/HYAL1/LYVE1, and leads to the protection from IDD. More interaction axes are to be exploited to provide theoretical bases for further study on IDD.
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Trissal, Maria, Jessica Silva, Todd Wylie, Jasreet Hundal, Sean McGrath, Vincent Magrini, Giridharan Ramsingh, Elaine R. Mardis, Timothy J. Ley, and Daniel C. Link. "Dysregulation and Recurrent Mutation Of miRNA-142 In De Novo AML." Blood 122, no. 21 (November 15, 2013): 472. http://dx.doi.org/10.1182/blood.v122.21.472.472.
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Altered microRNA (miRNA) expression is frequently observed in acute myelogenous leukemia (AML) and has been implicated in leukemic transformation., somatic mutation of miRNA genes appears to be rare in AML and cancer in general. We recently reported whole genome or exome sequencing of 200 cases of de novo AML (The Cancer Genome Atlas, NEJM 2013). Recurring point mutations of only one miRNA gene were identified. Specifically, heterozygous point mutations of MIR142 were identified in 3 cases and bi-allelic mutations were identified in 1 case (total incidence of 2%). The miRNA “seed” sequence, located at positions 2-8 from the 5’ end of the mature miRNA, is critical in mediating the specificity of miRNA-mRNA target interaction. Of import, all AML associated MIR142 point mutations localized to this critical seed region in the mature miRNA-142-3p sequence leading to the prediction that these mutations alter normal miRNA-142-3p function. Surprisingly, when we transiently over-expressed MIR142 mini-genes containing these mutations, we observed decreased expression of miR-142-5p, suggesting that the mutations in the seed sequence of miR-142-3p are affecting miRNA processing of the hairpin. To explore this possibility, we sequenced the small RNA transcriptome of 28 total cases of de novo AML, including the four cases harboring MIR142 point mutations. As a control, we also sequenced CD34+ progenitors from healthy donors (n = 4). In general, miRNA-142-5p is expressed at higher levels than 3p (average ratio of miRNA-142-5p/3p: 1.8 ± 0.23). However, in the three cases with heterozygous MIR142 mutations, a significantly decreased expression of miRNA-142-5p relative to 3p was observed (0.41± 0.13). Most strikingly, in the AML case with bi-allelic MIR142 mutations, miRNA-142-5p levels were markedly reduced. Of note, bioinformatic target prediction programs show the loss of many predicted miRNA-142-3p targets upon mutation. However, target prediction programs did not show any commonly gained mRNA targets between the three identified AML associated miRNA-142-3p mutants. Collectively, these data suggest that these MIR142 mutations are unlikely to be gain-of-function but probably lead to a complete loss of normal miRNA-142-3p function in addition to decreased processing or stability of miRNA-142-5p. Our small RNA sequencing data also revealed marked over-expression of miRNA-142 in our AML patient cohort. Compared with control CD34+ cells, miRNA-142-5p and 3p levels were increased 16.34 ± 3.6 and 30.92.34 ± 7.0 fold, respectively. Thus, we next examined the effects of enforced expression of wild-type or mutant MIR142 on hematopoiesis. C-kit+ murine hematopoietic progenitors transduced with lentivirus expressing wild-type or mutant MIR142 were transplanted into lethally irradiated recipients. Surprisingly, over-expression of wild type miRNA-142 resulted in a complete loss of repopulating activity as early as 6 wks post transplant. In contrast, hematopoietic progenitors transduced with mutant MIR142 were able to generate multi-lineage engraftment for at least 7 months post transplant. These data suggest that miRNA-142 over-expression in AML may be compensatory to transformation and serve to inhibit leukemic cell growth. It follows that the loss-of-function MIR142 observed in AML may disrupt this negative feedback loop, thereby promoting AML expansion. Studies to characterize the miRNA-142 target repertoire within the hematopoietic system are currently underway and should provide insights on how disruption of miRNA-142 function may contribute to the pathogenesis of AML. Disclosures: No relevant conflicts of interest to declare.
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Tseng, Kuan-Chieh, Yi-Fan Chiang-Hsieh, Hsuan Pai, Nai-Yun Wu, Han-Qin Zheng, Chi-Nga Chow, Tzong-Yi Lee, Song-Bin Chang, Na-Sheng Lin, and Wen-Chi Chang. "sRIS: A Small RNA Illustration System for Plant Next-Generation Sequencing Data Analysis." Plant and Cell Physiology 61, no. 6 (March 17, 2020): 1204–12. http://dx.doi.org/10.1093/pcp/pcaa034.
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Abstract Small RNA (sRNA), such as microRNA (miRNA) and short interfering RNA, are well-known to control gene expression based on degradation of target mRNA in plants. A considerable amount of research has applied next-generation sequencing (NGS) to reveal the regulatory pathways of plant sRNAs. Consequently, numerous bioinformatics tools have been developed for the purpose of analyzing sRNA NGS data. However, most methods focus on the study of sRNA expression profiles or novel miRNAs predictions. The analysis of sRNA target genes is usually not integrated into their pipelines. As a result, there is still no means available for identifying the interaction mechanisms between host and virus or the synergistic effects between two viruses. For the present study, a comprehensive system, called the Small RNA Illustration System (sRIS), has been developed. This system contains two main components. The first is for sRNA overview analysis and can be used not only to identify miRNA but also to investigate virus-derived small interfering RNA. The second component is for sRNA target prediction, and it employs both bioinformatics calculations and degradome sequencing data to enhance the accuracy of target prediction. In addition, this system has been designed so that figures and tables for the outputs of each analysis can be easily retrieved and accessed, making it easier for users to quickly identify and quantify their results. sRIS is available at http://sris.itps.ncku.edu.tw/.
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Susanti, R., Muchamad Dafip, and Dewi Mustikaningtyas. "OncomiR Structure and Network Prediction on Adenomatosis Polyposis Coli (APC) Gene Silencing Regulation in Colorectal Cancer." Trends in Sciences 20, no. 10 (August 15, 2023): 6168. http://dx.doi.org/10.48048/tis.2023.6168.
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The emergence of colorectal cancer cells is associated with the inactivation of the adenomatosis polyposis coli (APC) gene which increases the activity of ß-catenin, one of which is due to oncomiRNA (cancer-inducing microRNA). miR-135a/b-5p and miR-494-3p were thought to be involved in silencing the APC gene and increasing cell proliferation and could potentially be used as anti-miR targets. However, there is a need for an in-depth evaluation of the involvement of the oncomiR as a therapeutic target in preventing the formation of CRC. Therefore, this study aimed to predict the mechanism of inhibition of oncomiR hsa-miR-135a/b, and has-miR-494-3p against APC in the Wnt/ß-catenin signaling pathway. This research was conducted through in silico analysis using a web-based application to describe the stability of the secondary structure, binding position on mRNA, and conserved nucleotides that support biological activity. The data obtained were then used to develop miRNA interaction networks with APCs on the CRC-associated Wnt/ß-catenin signaling pathway. This study suggests that miR-135a-5p, and miR-135b-5p probably evolved earlier in the evolutionary evolution of the conserved oncomiR CRC in various vertebrate species, whereas miR-494-3p is more conserved and commonly found in mammals. The biological activity of miR-494-3p is likely to be more stable and patent to bind to APC gene mRNA and trigger CRC cell proliferation. Furthermore, miR-135a/b-5p and miR-494-3p have the potential to be developed as targets for anti-miR-based transcriptomic therapy as well as for early diagnosis of CRC development. Anti-miR therapy will likely need to involve more than 1 miRNA, as each gene has more than 1 miRNA binding site. HIGHLIGHTS Important findings in this study include: Adenomatosis polyposis coli (APC) gene silencing in CRC cases correlates to oncomiR activity of miR-135a/b-3p and miR-494-3p miR-494 tends to inhibit the translation of APC mRNA more strongly than miR-135a/b-5p represented by lower context++ score in mRNA binding simulation In some cases, CRC formation was also caused by silencing activity by oncomiRs, such as miR-135a-5p, miR-135b-5p and miR-494-3p which inhibited APC gene mRNA translation This study suggests that miR-135a-5p, and miR-135b-5p likely evolved earlier in the evolution of conserved CRC development in various vertebrate species, whereas miR-494-3p is more conserved and common in mammals Based on the biological activity miR-494-3p is likely to be more stable and potent to bind to the mRNA of the APC miR-135a/b-5p and miR-494-3p is potentially developed as targets for transcriptomic anti-miR-based therapy as well as for early diagnosis of CRC development GRAPHICAL ABSTRACT
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Li, Chao, Zhantong Hong, Miaoling Ou, Xiaodan Zhu, Linghua Zhang, and Xingkun Yang. "Integrated miRNA-mRNA Expression Profiles Revealing Key Molecules in Ovarian Cancer Based on Bioinformatics Analysis." BioMed Research International 2021 (October 25, 2021): 1–11. http://dx.doi.org/10.1155/2021/6673655.
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Ovarian cancer is one of the leading causes of gynecological malignancy-related deaths. The underlying molecular development mechanism has however not been elucidated. In this study, we used bioinformatics to reveal critical molecular and biological processes associated with ovarian cancer. The microarray datasets of miRNA and mRNA expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Besides, we performed target prediction of the identified differentially expressed miRNAs. The overlapped differentially expressed genes (DEGs) were obtained combined with miRNA targets predicted and the DEGs identified from the mRNA dataset. The Cytoscape software was used to design a regulatory network of miRNA-gene. Moreover, the overlapped DEGs in the network were subjected to enrichment analysis to explore the associated biological processes. The molecular protein-protein interaction (PPI) network was used to identify the key genes among the DEGs of prognostic value for ovarian cancer, and the genes were evaluated via Kaplan-Meier curve analysis. A total of 186 overlapped DEGs were identified. Through miRNA-gene network analysis, we found that miR-195-5p, miR-424-5p, and miR-497-5p highly exhibited targeted association with overlapped DEGs. The three miRNAs are critical in the regulatory network and act as tumor suppressors. The overlapped DEGs were mainly associated with protein metabolism, histogenesis, and development of the reproductive system and ocular tissues. The PPI network identified 10 vital genes that promote tumor progression. Survival analysis found that CEP55 and CCNE1 may be associated with the prognosis of ovarian cancer. These findings provide insights to understand the pathogenesis of ovarian cancer and suggest new candidate biomarkers for early screening of ovarian cancer.
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Ashraf, Fakiha, Muhammad Aleem Ashraf, Xiaowen Hu, and Shuzhen Zhang. "A novel computational approach to the silencing of Sugarcane Bacilliform Guadeloupe A Virus determines potential host-derived MicroRNAs in sugarcane (Saccharum officinarum L.)." PeerJ 8 (January 13, 2020): e8359. http://dx.doi.org/10.7717/peerj.8359.
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Sugarcane Bacilliform Guadeloupe A Virus (SCBGAV, genus Badnavirus, family Caulimoviridae) is an emerging, deleterious pathogen of sugarcane which presents a substantial barrier to producing high sugarcane earnings. Sugarcane bacilliform viruses (SCBVs) are one of the main species that infect sugarcane. During the last 30 years, significant genetic changes in SCBV strains have been observed with a high risk of disease incidence associated with crop damage. SCBV infection may lead to significant losses in biomass production in susceptible sugarcane cultivars. The circular, double-stranded (ds) DNA genome of SCBGAV (7.4 Kb) is composed of three open reading frames (ORFs) on the positive strand that replicate by a reverse transcriptase. SCBGAV can infect sugarcane in a semipersistent manner via the insect vectors sugarcane mealybug species. In the current study, we used miRNA target prediction algorithms to identify and comprehensively analyze the genome-wide sugarcane (Saccharum officinarum L.)-encoded microRNA (miRNA) targets against the SCBGAV. Mature miRNA target sequences were retrieved from the miRBase (miRNA database) and were further analyzed for hybridization to the SCBGAV genome. Multiple computational approaches—including miRNA-target seed pairing, multiple target positions, minimum free energy, target site accessibility, maximum complementarity, pattern recognition and minimum folding energy for attachments—were considered by all algorithms. Among them, sof-miR396 was identified as the top effective candidate, capable of targeting the vital ORF3 of the SCBGAV genome. miRanda, RNA22 and RNAhybrid algorithms predicted hybridization of sof-miR396 at common locus position 3394. The predicted sugarcane miRNAs against viral mRNA targets possess antiviral activities, leading to translational inhibition by mRNA cleavage. Interaction network of sugarcane-encoded miRNAs with SCBGAV genes, created using Circos, allow analyze new targets. The finding of the present study acts as a first step towards the creation of SCBGAV-resistant sugarcane through the expression of the identified miRNAs.
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Wu, Jiao, Shu Zhu, Chenyang Zhao, and Xiaoxue Xu. "A Comprehensive Investigation of Molecular Signatures and Pathways Linking Alzheimer’s Disease and Epilepsy via Bioinformatic Approaches." Current Alzheimer Research 19, no. 2 (February 2022): 146–60. http://dx.doi.org/10.2174/1567205019666220202120638.
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Background: Epileptic activity frequently occurs in patients with Alzheimer’s disease (AD), which may accelerate AD progression; however, the relationship between AD and epilepsy remains unclear. Objective: We aimed to investigate the molecular pathways and genes linking AD and epilepsy using bioinformatics approaches. Methods: Gene expression profiles of AD (GSE1297) and epilepsy (GSE28674) were derived from the Gene Expression Omnibus (GEO) database. The top 50% expression variants were subjected to weighted gene co-expression network analysis (WGCNA) to identify key modules associated with these diseases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses for the key modules were performed, and the intersected terms of functional enrichment and common genes within the key modules were selected. The overlapping genes were subjected to analyses of protein-protein interaction (PPI) network, transcription factor (TF)-mRNA network, microRNA (miRNA)-mRNA network, and drug prediction. Results: We identified 229 and 1187 genes in the AD-associated purple and epilepsy-associated blue modules, respectively. Six shared functional terms between the two modules included “calcium ion binding” and “calcium signaling pathway.” According to 17 common genes discovered, 130 TFmRNA pairs and 56 miRNA-mRNA pairs were established. The topological analyses of the constructed regulatory networks suggested that TF - FOXC1 and miRNA - hsa-mir-335-5p might be vital co-regulators of gene expression in AD and epilepsy. In addition, CXCR4 was identified as a hub gene, becoming the putative target for 20 drugs. Conclusion: Our study provided novel insights into the molecular connection between AD and epilepsy, which might be beneficial for exploring shared mechanisms and designing disease-modifying therapies.
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Feng, Wenxiao, Jie Yang, Wenchao Song, and Yitao Xue. "Crosstalk between Heart Failure and Cognitive Impairment via hsa-miR-933/RELB/CCL21 Pathway." BioMed Research International 2021 (September 18, 2021): 1–16. http://dx.doi.org/10.1155/2021/2291899.
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Background. The association between heart failure (HF) and cognitive impairment has received increasing attention from scholars and researchers in recent years. However, no systematic studies have been carried out yet focused on the crosstalk between heart failure and cognitive impairment via miRNAs. Methods. GSE104150, GSE53473, GSE120584, and GSE116250 with RNA-seq data and clinical data were downloaded from the GSE database. All data were statistically analysed using R software to detect DE-miRNAs and DE-mRNAs associated with both HF and cognitive impairment. Protein-protein interaction (PPI) networks were mapped, and a logistic regression model for cognitive impairment prediction was developed. Furthermore, the TTRUST database and miRWalk were used to map miRNA-transcription factor (TF) and messenger RNA (mRNA) regulatory pathways. Finally, core TFs were enriched for analysis. Results. Differentially enriched DE-miRNAs and DE-mRNAs both present in HF and cognitive impairment were determined. A logistic regression model established based on DE-miRNAs was validated to have a strong performance in cognitive impairment prediction. The core miRNA-TF-mRNA pathway was formed by mapping the PPI networks associated with the two diseases. Further GSEA was performed with V-rel reticuloendotheliosis viral oncogene homolog B (RELB) as the core TF, and the retinol metabolism and gap junction pathways were analysed. Conclusions. This study was the first attempt to predict the crosstalk and examine underlying mechanisms between HF and cognitive impairment applying bioinformatics. The findings suggested a potential hsa-miR-933/RELB/CCL21 regulatory axis correlated with HF and neurological disorders (or cognitive impairment), according to PPI networks.
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Khella, Heba W. Z., Marize Bakhet, Ghassan Allo, Michael A. S. Jewett, Andrew Girgis, Georg A. Bjarnason, and George M. Yousef. "Supression of tumor progression and metastasis in renal cell carcinoma by miR-192, miR-194, and miR-215." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 385. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.385.
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385 Background: miRNAs play a crucial rule in tumor progression and metastasis. We previously identified miR-192, miR-194 and miR-215 to be down-regulated in metastatic compared to primary clear cell renal cell carcinoma (ccRCC). In this work, we examine the role of miR-192, miR-194, and miR-215 in RCC progression and aggressiveness. Methods: We examined the role of these three miRNAs on tumor cell migration and invasion abilities using RCC cell line models. We performed target prediction analysis and experimentally validated the targets using independent approaches. In addition, we examined the clinical utility of miR-215 as a potential prognostic marker in RCC by measuring miR-215 expression using qRT-PCR in 61 formalin-fixed paraffin-embedded tissues from primary ccRCC and correlated the expression levels with clinical outcome. Results: Restoration of miR-192, miR-194, and miR-215 expression decreased cell migration and invasion in RCC cell lines. Target prediction analysis identified three potential targets of these miRNAs; MDM2, TYMS, and SIP1/ZEB2. We validated the miRNA-target interaction experimentally using three approaches. First by measuring the effect of miRNA overexpression on mRNA and protein levels of the predicted target, then by measuring the effect of miRNA overexpression on a luciferase signal of a vector containing the 3’UTR of the predicted target, and finally, by validating these interactions in vivoby examining the presence of an inverse correlation between miRNA changes and the expression levels of their targets on clinical specimens. In 61 patients with resected ccRCC tumors, we found that low miR-215 expression in the primary was associated with a significantly reduced recurrence-free survival. (26.4 vs. 49.2 months, respectively, p = 0.0320). Conclusions: Our analysis showed that miR-192, miR-194, and miR-215 are involved in RCC metastasis and that miR-215 predicts for recurrence in patients with resected RCC. Our findings pave the way to the clinical use of miRNAs as prognostic markers and potential therapeutic targets.
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Pallasch, Christian P., Michaela Patz, Yoon Jung Park, Susanne Hagist, Daniela Eggle, Rainer Claus, Svenja Debey-Pascher, et al. "Deregulation of miRNAs by Epigenetic Silencing Disrupts Suppression of the Oncogene PLAG1 in Chronic Lymphocytic Leukemia." Blood 114, no. 22 (November 20, 2009): 3463. http://dx.doi.org/10.1182/blood.v114.22.3463.3463.
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Abstract Abstract 3463 Poster Board III-351 MicroRNAs play a key role in cellular regulation and if deregulated in the development of neoplastic disorders including chronic lymphocytic leukemia (CLL). Both deregulations of miRNAs as well as the identification of their functional relevant targets and regulatory circuits in CLL pathogenesis are only partly understood and remain to be elucidated. RNAs from primary cells of 50 treatment-naïve CLL patients and peripheral B-cells of 14 healthy donors were applied to miRNA-expression profiling using bead chip technology. The majority of patients presented with Binet stage A disease and showed a favorable risk profile as assessed by clinical and molecular features. Comparing the total number of miRNA being expressed a significantly lower number of miRNA was detected in CLL compared to normal B cells. The predominance of down-regulated miRNAs in CLL cells was accompanied by highly significantly lower total number of miRNAs expressed above the detection threshold in CLL patients (19.8% vs 23.5%; p<10-6). In CLL cells a set of 7 up- and 19 down-regulated miRNAs was identified. We could not identify significant differentially expressed miRNA in cytogenetic defined subgroups, in particular we could not detect significant deregulation of miRNAs in patients harboring del13q14. Moreover, we could not identify significant down-regulation of miR-15 and miR-16 except in one patient harboring a homozygous deletion of chromosome 13q14. However, the previous up-regulation of miR-155, a key regulator of B-cell ontogenesis, appeared to be the most prominent up-regulated miRNA in our cohort. Interestingly, we identified so far unknown down-regulation of a set of miRNAs in CLL such as miR-107, -424, -125a, -126 and -326. Among the miRNAs being downregulated in CLL cells, 6 out of 10 miRNA promoters (miR-126, miR-139, miR-181a2/b2, miR-582, miR-107, miR-449) being examined showed gain of methylation as compared to normal B cell controls. Subsequent target prediction of deregulated miRNAs revealed a highly significant binding prediction at the 3′UTR of the pleomorphic adenoma gene 1 (PLAG1) oncogene. Luciferase reporter assays including site directed mutagenesis of binding sites revealed a significant regulation of PLAG1 by miR-181a, miR-181b, miR-107 and miR-424. While expression of PLAG1 mRNA was not affected, PLAG1 protein expression was shown to be significantly elevated in CLL cells as compared to the levels in healthy donor B cells. In conclusion we demonstrate (I) predominant down-regulation of miRNAs in CLL, (II) identified novel deregulated miRNAs in CLL, (III) unraveled underlying epigenetic changes in loci of deregulated miRNA, (IV) applied in silico target prediction of miRNA interactions for identification of novel pathogenetic factors, and (V) identified specific interaction of deregulated miRNA with PLAG1 3'UTRs resulting in over-expression of this oncogene in CLL. Therefore, PLAG1 over-expression in CLL cells represents a novel oncogenic mechanism in CLL pathogenesis on the background of deregulation in miRNA-mediated control mechanisms. Disclosures No relevant conflicts of interest to declare.
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Lu, Jia-Wei, Aimaier Rouzigu, Li-Hong Teng, and Wei-Li Liu. "The Construction and Comprehensive Analysis of Inflammation-Related ceRNA Networks and Tissue-Infiltrating Immune Cells in Ulcerative Colitis Progression." BioMed Research International 2021 (July 6, 2021): 1–20. http://dx.doi.org/10.1155/2021/6633442.
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Ulcerative colitis (UC) is a common disease with great variability in severity, with a high recurrence rate and heavy disease burden. In recent years, the different biological functions of competing endogenous RNA (ceRNA) networks of long noncoding RNAs (lncRNAs) and microRNAs (miRs) have aroused wide concerns, the ceRNA network of ulcerative colitis (UC) may have potential research value, and these expressed noncoding RNAs may be involved in the molecular basis of inflammation recurrence and progression. This study analyzed 490 colon samples associated with UC from 4 gene expression microarrays from the GEO database and identified gene modules by weighted correlation network analysis (WGCNA). CIBERSORT detected tissue-infiltrating leukocyte profiling by deconvolution of microarray data. LncBase and multiMIR were used to identify lncRNA-miRNA-mRNA interaction. We constructed a ceRNA network which includes 4 lncRNAs (SH3BP5-AS1, MIR4435-2HG, ENTPD1-AS1, and AC007750.1), 5 miRNAs (miR-141-3p, miR-191-5p, miR-192-5p, miR-194-5p, and miR196-5p), and 52 mRNAs. Those genes are involved in interleukin family signals, neutrophil degranulation, adaptive immunity, and cell adhesion pathways. lncRNA MIR4435-2HG is a variable in the decision tree for moderate-to-severe UC diagnostic prediction. Our work identifies potential regulated inflammation-related lncRNA-miRNA-mRNA regulatory axes. The regulatory axes are dysregulated during the deterioration of UC, suggesting that it is a risk factor for UC progression.
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Ashraf, Muhammad Aleem, Hafiza Kashaf Tariq, Xiao-Wen Hu, Jallat Khan, and Zhi Zou. "Computational Biology and Machine Learning Approaches Identify Rubber Tree (Hevea brasiliensis Muell. Arg.) Genome Encoded MicroRNAs Targeting Rubber Tree Virus 1." Applied Sciences 12, no. 24 (December 15, 2022): 12908. http://dx.doi.org/10.3390/app122412908.
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Tapping panel dryness (TPD), a complex physiological syndrome associated with the rubber tree (Hevea brasiliensis Muell. Arg.), causes cessation of latex drainage upon tapping and thus threatens rubber production. Rubber tree virus 1 (RTV1) is a novel positive-sense single-stranded RNA virus from the Betaflexiviridae (genus Capillovirus), which has been established to cause TPD. MicroRNAs (miRNAs) play an important role in the interplay between viruses and host cells. In this study, we identified the rubber tree genome-encoded miRNAs and their therapeutic targets against RTV1. We applied computational algorithms to predict target binding sites of rubber tree miRNAs potentially targeting RTV1 RNA genome. Mature rubber-tree miRNAs are retrieved from the miRBase database and are used for hybridization of the RTV1 genome. A total of eleven common rubber-tree miRNAs were identified based on consensus genomic positions. The consensus of four algorithms predicted the hybridization sites of the hbr-miR396a and hbr-miR398 at common genomic loci (6676 and 1840), respectively. A miRNA-regulatory network of rubber tree was constructed with the RTV1— ORFs using Circos, is illustrated to analyze therapeutic targets. Overall, this study provides the first computational evidence of the reliable miRNA–mRNA interaction between specific rubber tree miRNAs and RTV1 genomic RNA transcript. Therefore, the predicted data offer valuable evidence for the development of RTV1-resistant rubber tree in the future. Our work suggests that similar computational host miRNA prediction strategies are warranted for identification of the miRNA targets in the other viral genomes.
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Roy, Dipayan, Anupama Modi, and Purvi Purohit. "Interactome Profile of Visceral Adipose Tissue in Obesity Links Key Genes to Cancer Pathogenesis." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A51—A52. http://dx.doi.org/10.1210/jendso/bvab048.102.
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Abstract Obesity increases the risk of the development of several malignancies. The visceral adipose tissue (VAT) depot is one of the pivotal contributors behind the obesity-related pathogenetic mechanisms. In this study, we analyzed the differential gene expression profile in the VAT of obese children using two Gene Expression Omnibus datasets. GSE29718 and GSE9624 were sorted and 68 common differentially expressed genes (DEG) with fold change 1.5 upregulation or downregulation (cutoff |logFC|≥0.58496) were obtained. Gene ontology and functional enrichment and protein-protein interaction (PPI) network for the DEG were analyzed in Search Tool for the Retrieval of Interacting Genes (STRING), which revealed 37 biological processes, 3 cellular components, and 1 molecular function to be significantly associated. Reactome pathway analysis showed the DEG to be involved in- one carbon pool by folate, glycine degradation, transcriptional regulation by TP53, ERK inactivation, G1/S-specific transcription, Fanconi anemia pathway, beta-catenin phosphorylation cascade, RAF activation, and negative regulation of the MAPK pathway. The PPI network was set with a minimum interaction score of 0.400 and a maximum of 10 interactions, and it was significantly enriched (p-value 0.047) with 66 nodes and 46 edges. Target prediction was performed using miRNet. Several miRNA, including hsa-miR-1-3p, hsa-let-7b-5p, hsa-miR-16-5p, hsa-miR-27a-3p and hsa-miR-34a-5p were part of the mRNA-miRNA interaction network. Using the CytoHubba plugin in Cytoscape, the top 10 hub genes from the PPI network were discovered. Thymidine phosphorylase (TYMP) and dihydrofolate reductase (DHFR), essential components of nucleic acid metabolism, have been shown to be involved in angiogenesis and endothelial cell growth, and correlated to p53 mutations, respectively. Protein phosphatase 2, regulatory subunit A & regulatory subunit B (PPP2R1A and PPP2R1B) mutations are involved in ovarian, endometrial, lung and colorectal cancers. HLA-DQA1 mutation is involved cervical cancer, and it is involved in increased immune sensitivity and liver damage in breast cancer patients. The RAB7Ab and RAB7-interacting lysosomal protein (RILP) are regulators of endo-lysosomal trafficking and suppresses breast cancer cell invasion. To conclude, this study identifies several genes and their regulatory pathways in VAT which may contribute to the increased risk of cancer pathogenesis in obese individuals.
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Li, Baobao, Si Chen, Chengqiang Wang, Qiaoling Chen, Churiga Man, Qi An, Zhenxing Zhang, Zhiyong Liu, Li Du, and Fengyang Wang. "Integrated mRNA-seq and miRNA-seq analysis of goat fibroblasts response to Brucella Melitensis strain M5-90." PeerJ 9 (June 29, 2021): e11679. http://dx.doi.org/10.7717/peerj.11679.
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Brucellosis is a globally zoonotic bacterial disease of humans and various animals including goats, sheep, and cattle. Brucella melitensis M5-90, a live attenuated vaccine strain, has been widely used to prevent brucellosis in goats and sheep. However, the molecular mechanisms governing protective immunity response in non-professional phagocytes infected with B. melitensis M5-90 have not been fully investigated, especially in goats. In our research, goat fibroblasts were used as in vitro models to determine these mechanisms by transcriptome analysis. After incubating with B. melitensis M5-90 3 h, the infected goat fibroblasts were collected at 0 h, 4 h, 24 h, 48 h and 72 h for RNA-seq. The results indicated that there were totally 11,819 differentially expressed genes (DEGs) and 777 differentially expressed (DE) miRNAs found in experiment groups compared with the control groups (|log2(Foldchange)|≥1, FDR<0.05). GO and KEGG enrichment analyses revealed that down-regulated genes were involved in the riboflavin metabolism and positive regulation of IL-8 secretion pathway. The up-regulated genes were mainly involved in adaptive immunity, including TNF signaling pathway, MAPK signaling pathway and JAK/STAT pathway. Additionally, cytokine-cytokine receptor interaction, natural killer cell mediated cytotoxicity and toll-like receptor signaling pathway, which associated with innate immunity pathways, were also induced. Based on the Pearson correlation coefficients and prediction results of TargetScan and miRanda, the miRNA-mRNA networks of NFKB1, IFNAR2 and IL10RB were constructed and verified in goat fibroblasts by qPCR, which demonstrated that goat fibroblasts displayed immunomodulatory properties. Our findings provide a deeper insight into the host miRNA-driven B. melitensis defense mechanism and reveal the transcriptome changes involved in the innate and adaptive immune response of the goats to B. melitensis infection.
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Ghadiri, Nooshin, Aref Hoseini, Kamran Ghaedi, Negar Alsadat Emamnia, Mazdak Ganjalikhani-Hakemi, Parnian Navabi, Hedyatollah Shirzad, and Mohammad Hossein Nasr-Esfahani. "Prediction of probable impact of miR-34a and miR-215 on differentiation of naive CD4+ T cells to Th17 cells in multiple sclerosis." Journal of Shahrekord University of Medical Sciences 21, no. 6 (December 28, 2018): 276–79. http://dx.doi.org/10.34172/jsums.2019.48.
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Background and aims: miRNAs, as a class of non-coding RNAs, take part in different cellular processes. Dysregulation of different miRNAs has been reported in numerous disorders to date. Multiple sclerosis (MS) is an autoimmune disease with high prevalence in Iran and Th17 cells play an important role in its pathogenesis. In the current study, we aimed to predict the possible role of miR-34a and miR-215 in the process of controlling Th17 differentiation, and hence, their possible impact on the onset and progression of MS. Methods: We investigated probable interactions of miRNAs and genes that participate in Th17 cells differentiation using miRwalk database as an integrative one which utilizes 10 different algorithms to predict miRNA-mRNA interaction. Results: Based on our findings, miR-34a and miR-215 were predicted to have a potential role in the induction of Th17 cells differentiation. Conclusion: Conclusively, miR-34a and miR-215 may up-regulate Th17 cells of MS patients. Since bioinformatics data have shown that these miRNAs suppress negative regulatory genes in Th17 cells differentiation, we suppose that down-regulation of these miRNAs could ameliorate MS symptoms. Therefore, several therapeutic approaches may be considered for these miRNAs besides their application as valuable prognostic/diagnostic biomarkers in detection of various stages of MS.
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Harquail, Jason, Nicolas LeBlanc, Rodney J. Ouellette, and Gilles A. Robichaud. "miRNAs 484 and 210 regulate Pax-5 expression and function in breast cancer cells." Carcinogenesis 40, no. 8 (January 3, 2019): 1010–20. http://dx.doi.org/10.1093/carcin/bgy191.
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AbstractRecent studies have enabled the identification of important factors regulating cancer progression, such as paired box gene 5 (Pax-5). This transcription factor has consistently been associated to B-cell cancer lesions and more recently solid tumors including breast carcinoma. Although Pax-5 downstream activity is relatively well characterized, aberrant Pax-5 expression in a cancer-specific context is poorly understood. To investigate the regulation of Pax-5 expression, we turned to micro RNAs (miRNAs), small non-coding RNA molecules that regulate key biological processes. Extensive studies show that miRNA deregulation is prevalent in cancer lesions. In this study, we aim to elucidate a causal link between differentially expressed miRNAs in cancer cells and their putative targeting of Pax-5-dependent cancer processes. Bioinformatic prediction tools indicate that miRNAs 484 and 210 are aberrantly expressed in breast cancer and predicted to target Pax-5 messenger RNA (mRNA). Through conditional modulation of these miRNAs in breast cancer cells, we demonstrate that miRNAs 484 and 210 inhibit Pax-5 expression and regulate Pax-5-associated cancer processes. In validation, we show that these effects are probably caused by direct miRNA/mRNA interaction, which are reversible by Pax-5 recombinant expression. Interestingly, miRNAs 484 and 210, which are both overexpressed in clinical tumor samples, are also modulated during epithelial–mesenchymal transitioning and hypoxia that correlate inversely to Pax-5 expression. This is the first study demonstrating the regulation of Pax-5 expression and function by non-coding RNAs. These findings will help us better understand Pax-5 aberrant expression within cancer cells, creating the possibility for more efficient diagnosis and treatments for cancer patients.
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Yuan, Qin, Zilu Wen, Ke Yang, Shulin Zhang, Ning Zhang, Yanzheng Song, and Fuxue Chen. "Identification of Key CircRNAs Related to Pulmonary Tuberculosis Based on Bioinformatics Analysis." BioMed Research International 2022 (April 4, 2022): 1–15. http://dx.doi.org/10.1155/2022/1717784.
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Pulmonary tuberculosis (TB) is a chronic infectious disease that is caused by respiratory infections, principally Mycobacterium tuberculosis. Increasingly, studies have shown that circular (circ)RNAs play regulatory roles in different diseases through different mechanisms. However, their roles and potential regulatory mechanisms in pulmonary TB remain unclear. In this study, we analyzed circRNA sequencing data from adjacent normal and diseased tissues from pulmonary TB patients and analyzed the differentially expressed genes. We then constructed machine learning models and used single-factor analysis to identify hub circRNAs. We downloaded the pulmonary TB micro (mi)RNA (GSE29190) and mRNA (GSE83456) gene expression datasets from the Gene Expression Omnibus database and performed differential expression analysis to determine the differentially expressed miRNAs and mRNAs. We also constructed a circRNA–miRNA–mRNA interaction network using Cytoscape. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to predict the biological functions of the identified RNAs and determine hub genes. Then, the STRING database and cytoHubba were used to construct protein-protein interaction networks. The results showed 125 differentially expressed circRNAs in the adjacent normal and diseased tissues of pulmonary TB patients. Among them, we identified three hub genes associated with the development of pulmonary TB: hsa_circ_0007919 (upregulated), hsa_circ_0002419 (downregulated), and hsa_circ_0005521 (downregulated). Through further screening, we determined 16 mRNAs of potential downstream genes for hsa-miR-409-5p and hsa_circ_0005521 and established an interaction network. This network may have important roles in the occurrence and development of pulmonary TB. We constructed a model with 100% prediction accuracy by machine learning and single-factor analysis. We constructed a protein-protein interaction network among the top 50 hub mRNAs, with FBXW7 scoring the highest and SOCS3 the second highest. These results may provide a new reference for the identification of candidate markers for the early diagnosis and treatment of pulmonary TB.
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Prinz, Christian, Kemal Mese, and David Weber. "MicroRNA Changes in Gastric Carcinogenesis: Differential Dysregulation during Helicobacter pylori and EBV Infection." Genes 12, no. 4 (April 19, 2021): 597. http://dx.doi.org/10.3390/genes12040597.
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Despite medical advances, gastric-cancer (GC) mortality remains high in Europe. Bacterial infection with Helicobacter pylori (H. pylori) and viral infection with the Epstein–Barr virus (EBV) are associated with the development of both distal and proximal gastric cancer. Therefore, the detection of these infections and the prediction of further cancer development could be clinically significant. To this end, microRNAs (miRNAs) could serve as promising new tools. MiRNAs are highly conserved noncoding RNAs that play an important role in gene silencing, mainly acting via translational repression and the degradation of mRNA targets. Recent reports demonstrate the downregulation of numerous miRNAs in GC, especially miR-22, miR-145, miR-206, miR-375, and miR-490, and these changes seem to promote cancer-cell invasion and tumor spreading. The dysregulation of miR-106b, miR-146a, miR-155, and the Let-7b/c complex seems to be of particular importance during H. pylori infection or gastric carcinogenesis. In contrast, many reports describe changes in host miRNA expression and outline the effects of bamHI-A region rightward transcript (BART) miRNA in EBV-infected tissue. The differential regulation of these miRNA, acting alone or in close interaction when both infections coexist, may therefore enable us to detect cancer earlier. In this review, we focus on the two different etiologies of gastric cancer and outline the molecular pathways through which H. pylori- or EBV-induced changes might synergistically act via miR-155 dysregulation to potentiate cancer risk. The three markers, namely, H. pylori presence, EBV infection, and miR-155 expression, may be checked in routine biopsies to evaluate the risk of developing gastric cancer.
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Quilang, Rachel C., Sylvia Lui, and Karen Forbes. "miR-514a-3p: a novel SHP-2 regulatory miRNA that modulates human cytotrophoblast proliferation." Journal of Molecular Endocrinology 68, no. 2 (February 1, 2022): 99–110. http://dx.doi.org/10.1530/jme-21-0175.
Full textAbstract:
Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP-2), encoded by the PTPN11 gene, forms a central component of multiple signalling pathways and is required for insulin-like growth factor (IGF)-induced placental growth. Altered expression of SHP-2 is associated with aberrant placental and fetal growth indicating that drugs modulating SHP-2 expression may improve adverse pregnancy outcome associated with altered placental growth. We have previously demonstrated that placental PTPN11/SHP-2 expression is controlled by miRNAs. SHP-2 regulatory miRNAs may have therapeutic potential; however, the individual miRNA(s) that regulate SHP-2 expression in the placenta remain to be established. We performed in silico analysis of 3’UTR target prediction databases to identify libraries of Hela cells transfected with individual miRNA mimetics, enriched in potential SHP-2 regulatory miRNAs. Analysis of PTPN11 levels by quantitative (q) PCR revealed that miR-758-3p increased, while miR-514a-3p reduced PTPN11 expression. The expression of miR-514a-3p and miR-758-3p within the human placenta was confirmed by qPCR; miR-514a-3p (but not miR-758-3p) levels inversely correlated with PTPN11 expression. To assess the interaction between these miRNAs and PTPN11/SHP-2, specific mimetics were transfected into first-trimester human placental explants and then cultured for up to 4 days. Overexpression of miR-514a-3p, but not miR-758-3p, significantly reduced PTPN11 and SHP-2 expression. microRNA-ribonucleoprotein complex (miRNP)-associated mRNA assays confirmed that this interaction was direct. miR-514a-3p overexpression attenuated IGF-I-induced trophoblast proliferation (BrdU incorporation). miR-758-3p did not alter trophoblast proliferation. These data demonstrate that by modulating SHP-2 expression, miR-514a-3p is a novel regulator of IGF signalling and proliferation in the human placenta and may have therapeutic potential in pregnancies complicated by altered placental growth.
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Movassagh, Mercedeh, Sarah U. Morton, Christine Hehnly, Jasmine Smith, Trang T. Doan, Rafael Irizarry, James R. Broach, Steven J. Schiff, Jeffrey A. Bailey, and Joseph N. Paulson. "mirTarRnaSeq: An R/Bioconductor Statistical Package for miRNA-mRNA Target Identification and Interaction Analysis." BMC Genomics 23, no. 1 (June 13, 2022). http://dx.doi.org/10.1186/s12864-022-08558-w.
Full textAbstract:
AbstractWe introduce mirTarRnaSeq, an R/Bioconductor package for quantitative assessment of miRNA-mRNA relationships within sample cohorts. mirTarRnaSeq is a statistical package to explore predicted or pre-hypothesized miRNA-mRNA relationships following target prediction.We present two use cases applying mirTarRnaSeq. First, to identify miRNA targets, we examined EBV miRNAs for interaction with human and virus transcriptomes of stomach adenocarcinoma. This revealed enrichment of mRNA targets highly expressed in CD105+ endothelial cells, monocytes, CD4+ T cells, NK cells, CD19+ B cells, and CD34 cells. Next, to investigate miRNA-mRNA relationships in SARS-CoV-2 (COVID-19) infection across time, we used paired miRNA and RNA sequenced datasets of SARS-CoV-2 infected lung epithelial cells across three time points (4, 12, and 24 hours post-infection). mirTarRnaSeq identified evidence for human miRNAs targeting cytokine signaling and neutrophil regulation immune pathways from 4 to 24 hours after SARS-CoV-2 infection. Confirming the clinical relevance of these predictions, three of the immune specific mRNA-miRNA relationships identified in human lung epithelial cells after SARS-CoV-2 infection were also observed to be differentially expressed in blood from patients with COVID-19. Overall, mirTarRnaSeq is a robust tool that can address a wide-range of biological questions providing improved prediction of miRNA-mRNA interactions.
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Pianfetti, Elena, Marta Lovino, Elisa Ficarra, and Loredana Martignetti. "MiREx: mRNA levels prediction from gene sequence and miRNA target knowledge." BMC Bioinformatics 24, no. 1 (November 22, 2023). http://dx.doi.org/10.1186/s12859-023-05560-1.
Full textAbstract:
AbstractMessenger RNA (mRNA) has an essential role in the protein production process. Predicting mRNA expression levels accurately is crucial for understanding gene regulation, and various models (statistical and neural network-based) have been developed for this purpose. A few models predict mRNA expression levels from the DNA sequence, exploiting the DNA sequence and gene features (e.g., number of exons/introns, gene length). Other models include information about long-range interaction molecules (i.e., enhancers/silencers) and transcriptional regulators as predictive features, such as transcription factors (TFs) and small RNAs (e.g., microRNAs - miRNAs). Recently, a convolutional neural network (CNN) model, called Xpresso, has been proposed for mRNA expression level prediction leveraging the promoter sequence and mRNAs’ half-life features (gene features). To push forward the mRNA level prediction, we present miREx, a CNN-based tool that includes information about miRNA targets and expression levels in the model. Indeed, each miRNA can target specific genes, and the model exploits this information to guide the learning process. In detail, not all miRNAs are included, only a selected subset with the highest impact on the model. MiREx has been evaluated on four cancer primary sites from the genomics data commons (GDC) database: lung, kidney, breast, and corpus uteri. Results show that mRNA level prediction benefits from selected miRNA targets and expression information. Future model developments could include other transcriptional regulators or be trained with proteomics data to infer protein levels.