Volume 2022, Issue 1 9264555
Research Article
Open Access

Identification of Differentially Expressed microRNAs Associated with Ischemic Stroke by Integrated Bioinformatics Approaches

Shengqiang Jiang

Shengqiang Jiang

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China fimmu.com

Department of Neurosurgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China gd2h.com

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Jie Wu

Jie Wu

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China fimmu.com

Department of Neurosurgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China gd2h.com

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Yan Geng

Yan Geng

Department of Neurosurgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China gd2h.com

School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China gdut.edu.cn

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Yuting Zhang

Yuting Zhang

School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China gdut.edu.cn

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Yupeng Wang

Yupeng Wang

School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China gdut.edu.cn

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Jinrong Wu

Jinrong Wu

School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China gdut.edu.cn

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Chunqu Lu

Chunqu Lu

Department of Outpatient, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China gd2h.com

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Guoxuan Luo

Guoxuan Luo

Department of Neurosurgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China gd2h.com

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Jie Zan

Corresponding Author

Jie Zan

Department of Neurosurgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China gd2h.com

School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China gdut.edu.cn

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Yong Zhang

Corresponding Author

Yong Zhang

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China fimmu.com

Department of Neurosurgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China gd2h.com

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First published: 10 October 2022
Academic Editor: Luca Falzone

Abstract

Ischemic stroke (IS) is one of the leading causes of disability and mortality worldwide. This study aims to find the crucial exosomal miRNAs associated with IS by using bioinformatics methods, reveal potential biomarkers for IS, and investigate the association between the identified biomarker and immune cell pattern in the peripheral blood of IS patients. In this study, 3 up-regulated miRNAs (hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p) miRNAs in the serum exosomes between IS patients and healthy controls from GEO database (GSE199942) and 25 down-regulated genes of peripheral blood mononuclear cells of IS patients from GSE22255 were obtained with the help of the R software. GO annotation and KEGG pathway enrichment analysis showed that the 25 down-regulated genes were associated with coenzyme metabolic process and were mainly enriched in the N-glycan biosynthesis pathway. Furthermore, we performed the LASSO algorithm to narrow down the above 25 intersected genes, and identified 8 key genes which had a good diagnostic value in discriminating IS patients from the healthy controls analyzed with ROC curve. CIBERSORT algorithm indicated that the abundance of M0 macrophages and resting mast cells was significantly lower than that of the control group. The spearman correlation analysis showed that STT3A was negatively correlated with the proportion of follicular helper T cells, activated NK cells and resting dendritic cells. Finally, GSE117064 showed that has-miR-16-5p was more advantageous for diagnosing stroke. In conclusion, hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p are identified as specific related exosomal miRNAs for IS patients. These genes may provide new targets for the early identification of IS.

1. Introduction

Ischemic stroke (IS) is one of the leading causes of disability and mortality worldwide and accounts for 80% of all strokes [1]. Intravenous thrombolysis is the only approved treatment strategy for acute IS by FDA [2]. Due to the short treatment time window within 4.5 h of onset and the high risk of hemorrhage, the thrombolysis rate in IS patients is very low [3], suggesting early diagnosis is extremely critical. Nowadays, clinical diagnosis of IS mainly relies on magnetic resonance imaging and computed tomography [4]. However, most community medical institutions lack the testing equipment, and the brain imaging examinations are relatively expensive, which limits the clinical diagnosis of IS [5]. Thus, developing new diagnostic markers and therapeutic targets for IS are urgently needed.

microRNAs (miRNAs) are a class of small and noncoding RNA, which regulate gene expression through silencing target genes and play important roles in the nervous system diseases, such as traumatic brain injury, spinal cord injury, subarachnoid hemorrhage, and IS [68]. For example, miR-31 inhibits traumatic brain injury-triggered neuronal cell apoptosis by regulating hypoxia-inducible factor-1A/vascular endothelial growth factor A axis [7]. miR-672-3p promotes functional recovery in rats with contusive spinal cord injury by inhibiting ferroptosis suppressor protein 1 [8]. Nowadays, more and more studies identify that some aberrant expressed circulating miRNAs in the serum, which are identified via bioinformatics methods, could be used as potential candidates for disease diagnosis. For example, Hsa-miR-484, hsa-miR-185-5p, hsa-miR-340-5p, hsa-miR-146a-5p, and hsa-miR-195-5p have a prognostic value in breast cancer patients treated with integrative interventions, including diet and physical activity [9]. Specific alteration of 20 miRNAs has a direct association with pesticide exposure and the development of neurodegenerative diseases [10]. Hsa-miR-181a-3p, hsa-miR-214-3p, hsa-miR-18a-5p, and hsa-miR-938 are positively related to the IL-6 signaling pathway activation in various cancers [11]. 14 potentially important miRNAs are identified as IS diagnostic signatures via bioinformatics method combined with logistic regression analysis [12]. Whereas circulating miRNAs in the serum are generally affected by the different pathophysiological conditions and circulating ribonucleases [13], there are still short of reliable prognostic or diagnostic blood biomarkers.

Exosomes are spherical extracellular nanovesicles with a bilayer lipid structure for the outer membrane, defined by a diameter of 30–100 nm [14]. Exosomes contain proteins, mRNAs, and miRNAs and play essential roles in intercellular communication [15]. Due to their high stability, serum exosomal miRNAs are considered to be powerful non-invasive biomarkers in many diseases, including breast cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma [1618]. Recently, Tong et al. [19] found that miR-151a-5p, miR-24, mir-485-5p, mir-331-5p, and mir-214 were upregulated with statistical significance in both the serum exosome and cerebrospinal fluid exosomes, and may be considered as a biomarker for the diagnosis of Parkinson’s disease.

In this study, we attempt to identify the crucial exosomal miRNAs associated with IS by using bioinformatics methods, reveal potential biomarkers for IS, and investigate the association between the identified biomarker and immune cell infiltration in IS.

2. Materials and Methods

2.1. Data Sources

The data were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo). The inclusion and exclusion criteria for these data sets were as follows. Inclusion criteria: (i) data sets containing miRNA and mRNA expression levels of IS patients; (ii) data sets reporting miRNAs expression levels of both IS patient and healthy patient; and (iii) data sets containing miRNA expression data of at least 5 IS samples and 5 controls. Exclusion criteria: (i) data sets containing exclusively IS sample and (ii) data sets containing miRNAs expression levels of animal models, cell lines or other in vitro experiments.

GSE199942 included the miRNA expression profiles of serum exosomes in five acute IS patients and five healthy controls detected by RNA-seq using llumina HiSeqTM 2500. GSE22255 included the gene expression profiling in peripheral blood mononuclear cells (PBMCs) of 20 IS patients and 20 sex- and age-matched controls using Affymetrix microarrays. GSE16561 included the gene expression profiles of peripheral whole blood RNA from 39 IS patients and 24 healthy controls. GSE117064 included the microRNA profiles of 1785 samples, which consist of 173 of CVD patients, 1612 of non-CVD control using microarrays. PMC8702168 included the miRNA expression profiles of human stroke brain tissue in five acute IS patients and three non-stroke controls detected by RNA-seq using Illumina NextSeq 500. All the data sets used in this study could be available on GEO data sets.

2.2. Analysis of Differentially Expressed miRNAs and Genes

The differentially expressed miRNAs from GSE199942 were obtained using the edgeR package [20]. The differentially expressed genes from GSE22255 were obtained using the limma package [21]. The P value <0.05 was used as threshold for nominally significant differential expression. gplot2 and pheatmap packages were used to draw the volcanic maps and heat maps, respectively.

2.3. Sankey Diagram of the miRNAs-mRNAs Network

The miRNAs-mRNAs network was drawn using the “ggalluvial” package of R software.

2.4. GO and KEGG Analysis

Gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed using the “clusterProfiler” R package [22]. P value <0.05 was considered the criterion for statistical significance.

2.5. Evaluation of Immune Cell Abundance

The gene expression profiling of GSE22255 was used to compare immune cell abundance in the peripheral blood of 20 IS patients and 20 healthy controls. The “CIBERSORT” algorithm was used to calculate the relative proportions of 22 types of immune cells [23]. Significant alterations in immune cells were identified using the Wilcoxon test at P < 0.05. The “ggcorrplot” package was used to visualize the results of correlation between immune cells.

2.6. Diagnostic Value of Differentially Expressed Genes in IS

The receiver operating characteristic (ROC) curve analysis is often used to determine the best diagnostic threshold for a diagnostic method. Generally, the area under the curve (AUC) value of >0.7 obtained from ROC curve analysis is considered to have a good predictive value [24].

3. Results

3.1. Identification of Differentially Expressed Exosomal miRNAs Related to IS

In this study, we analyzed the differentially expressed miRNAs in serum exosomes between IS patients and healthy controls from GSE199942 data sets, and found that 35 upregulated and 24 downregulated miRNAs (Table 1). The expression of these miRNAs is shown in Figures 1(a) and 1(b). Furthermore, the differentially expressed serum exosomes miRNAs were intersected with those differentially expressed miRNAs from freshly removed human stroke brain tissue [25], and three upregulated miRNAs were obtained: hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p (Figures 1(c) and 1(d)).

1. The differentially expressed miRNAs in serum exosomes between IS patients and healthy controls from GSE199942 data sets.
Genes logFC logCPM P Value FDR Change
hsa-miR-4511 4.0177751 3.1519311 0.000391 0.1276672 Up
hsa-miR-450a-5p 2.3608531 4.75 0.0018718 0.2345272 Up
hsa-miR-15b-5p 1.8701565 5.6824497 0.0027574 0.2345272 Up
hsa-miR-187-3p 6.0409799 3.6370248 0.0028732 0.2345272 Up
hsa-miR-4488 3.107022 5.1401173 0.0049058 0.2367778 Up
hsa-miR-30a-5p 2.4603292 10.202389 0.0051825 0.2367778 Up
hsa-miR-3688-3p 4.5127781 1.9219509 0.0054893 0.2367778 Up
hsa-miR-30a-3p 2.3492478 7.3137497 0.0057183 0.2367778 Up
hsa-miR-519b-5p 5.5515639 2.2856343 0.0067765 0.2367778 Up
hsa-miR-523-5p 5.5515635 2.2856343 0.0067769 0.2367778 Up
hsa-miR-522-5p 5.5515236 2.2856343 0.0068149 0.2367778 Up
hsa-miR-518e-5p 5.55147 2.2856343 0.0068664 0.2367778 Up
hsa-miR-519c-5p 5.5514537 2.2856343 0.0068822 0.2367778 Up
hsa-miR-519a-5p 5.5513848 2.2856343 0.0069491 0.2367778 Up
hsa-miR-23a-3p 1.3900129 8.9137221 0.0073152 0.2367778 Up
hsa-miR-223-3p 1.6990938 6.5924347 0.0076146 0.2367778 Up
hsa-miR-1262 4.7679363 1.8418462 0.0090333 0.2564662 Up
hsa-miR-184 3.9283866 3.4873381 0.0096432 0.2623126 Up
hsa-let-7g-3p 4.777119 1.8349666 0.010846 0.2623126 Up
hsa-miR-503-5p 1.4637255 5.9719843 0.011694 0.2727198 Up
hsa-miR-2115-3p 3.3598963 2.5755635 0.0141269 0.3180986 Up
hsa-miR-365a-3p 3.3751344 3.1958665 0.0210196 0.4111132 Up
hsa-miR-365b-3p 3.3752176 3.1958665 0.0213312 0.4111132 Up
hsa-miR-143-3p 1.3106202 12.340244 0.0232167 0.4123441 Up
hsa-miR-140-3p 1.1006504 13.62317 0.0239955 0.4123441 Up
hsa-miR-4677-3p 2.6511654 2.7753844 0.0247074 0.4136901 Up
hsa-miR-708-3p 1.5837876 4.899895 0.0268826 0.4341984 Up
hsa-miR-518d-5p 4.5933127 1.7706809 0.0284491 0.4341984 Up
hsa-miR-520c-5p 4.5932967 1.7706809 0.0284886 0.4341984 Up
hsa-miR-526a 4.5932549 1.7706809 0.0285919 0.4341984 Up
hsa-miR-16-5p 1.1811937 10.014053 0.0295433 0.4384491 Up
hsa-miR-873-5p 2.7302829 3.6544356 0.0305988 0.4440228 Up
hsa-miR-218-5p 1.673055 4.8719318 0.0327228 0.4546377 Up
hsa-miR-542-3p 1.702724 4.0029647 0.0387468 0.4914672 Up
hsa-miR-501-5p 2.6408656 1.9304482 0.0466 0.5261696 Up
hsa-miR-185-5p –0.995934 14.161013 0.0511742 0.5569459 No significant change
hsa-miR-206 –1.392741 5.7462987 0.0633447 0.6573682 No significant change
hsa-miR-7113-5p 3.8099703 1.6612046 0.0652589 0.6573682 No significant change
hsa-miR-509-3-5p 3.3464599 2.1064268 0.0670369 0.6573682 No significant change
hsa-miR-548ad-5p 1.5915279 4.2304639 0.0679466 0.6573682 No significant change
hsa-miR-548ae-5p 1.5915235 4.2304639 0.0684497 0.6573682 No significant change
hsa-miR-107 0.9647205 7.8566926 0.069841 0.6573682 No significant change
hsa-miR-6511b-5p –1.909183 3.2621364 0.0716849 0.6573682 No significant change
hsa-miR-6741-3p –2.264989 2.2929563 0.0723131 0.6573682 No significant change
hsa-miR-145-3p 1.0398494 6.7240529 0.0723487 0.6573682 No significant change
hsa-miR-204-3p 1.6478542 5.208978 0.0728423 0.6573682 No significant change
hsa-miR-330-3p –0.869386 7.1790501 0.0731215 0.6573682 No significant change
hsa-miR-4762-3p –2.799118 2.0076936 0.0754312 0.6573682 No significant change
hsa-miR-589-5p 0.8636502 6.1429256 0.0773701 0.6573682 No significant change
hsa-miR-671-3p –1.041089 5.1409541 0.0790674 0.6573682 No significant change
hsa-miR-323b-3p 2.2265637 3.0213546 0.0792916 0.6573682 No significant change
hsa-miR-125a-5p –1.112356 7.7678399 0.0798332 0.6573682 No significant change
hsa-miR-141-3p –2.577872 2.3667262 0.0800967 0.6573682 No significant change
hsa-miR-3913-5p 1.0922674 4.8446192 0.0813834 0.6573682 No significant change
hsa-miR-378c –1.333366 9.2448839 0.0814884 0.6573682 No significant change
hsa-miR-744-5p –0.797828 9.5563371 0.0822931 0.6573682 No significant change
hsa-miR-148a-5p –1.102375 5.6535438 0.0842296 0.6573682 No significant change
hsa-miR-5193 –2.996555 1.7341056 0.084313 0.6573682 No significant change
hsa-miR-1224-5p –1.333808 5.0287236 0.0856865 0.6573682 No significant change
hsa-miR-1298-5p 2.1271815 2.4541849 0.0863259 0.6573682 No significant change
hsa-miR-548ay-5p 1.480535 3.4698845 0.0885952 0.6573682 No significant change
hsa-miR-326 –1.490204 3.2492 0.0888616 0.6573682 No significant change
hsa-miR-4755-5p –1.963428 2.9818739 0.0889711 0.6573682 No significant change
hsa-miR-331-5p 1.3601536 3.3388849 0.0891202 0.6573682 No significant change
hsa-miR-27a-5p 0.9183589 6.5858081 0.0914764 0.6573682 No significant change
hsa-miR-3928-3p –1.271881 5.1073389 0.0930995 0.6573682 No significant change
hsa-miR-509-3p 3.1073088 2.4748986 0.0935276 0.6573682 No significant change
hsa-miR-3157-3p 1.6474404 2.5354758 0.0939205 0.6573682 No significant change
hsa-miR-6810-5p –4.812779 1.8099467 0.0941476 0.6573682 No significant change
hsa-miR-27a-3p 1.0144034 9.7833195 0.0946288 0.6573682 No significant change
hsa-miR-15b-3p 1.8701193 3.380578 0.0968837 0.6590269 No significant change
hsa-miR-34a-5p 4.1686458 1.6079117 0.0977092 0.6590269 No significant change
hsa-miR-3130-3p 1.5038518 3.6004664 0.099497 0.6590269 No significant change
hsa-miR-371a-5p –4.337354 1.6313631 0.0995531 0.6590269 No significant change
hsa-miR-1292-5p –1.033145 5.8012275 0.1007279 0.6590269 No significant change
hsa-miR-214-3p 1.6997602 2.9803798 0.1017758 0.6590269 No significant change
hsa-miR-1307-3p –0.862513 10.95775 0.1019322 0.6590269 No significant change
hsa-miR-1246 1.0685772 11.120133 0.1060379 0.6612336 No significant change
hsa-miR-6747-3p –2.403327 1.9904787 0.1087132 0.6612336 No significant change
hsa-miR-6857-3p –2.313114 1.8454211 0.1093797 0.6612336 No significant change
hsa-miR-6859-5p –1.293482 3.0140416 0.1099169 0.6612336 No significant change
hsa-miR-2277-3p –4.486188 1.684403 0.1104925 0.6612336 No significant change
hsa-miR-1273h-3p –1.024439 4.7744306 0.1125173 0.6612336 No significant change
hsa-miR-4489 –1.652656 2.8115404 0.1157286 0.6612336 No significant change
hsa-miR-2110 –0.763399 9.533566 0.1160144 0.6612336 No significant change
hsa-miR-582-3p 0.9692591 6.8717413 0.1178804 0.6612336 No significant change
hsa-miR-421 1.1333857 3.7603465 0.1179684 0.6612336 No significant change
hsa-miR-6808-3p –1.864298 2.0341099 0.118289 0.6612336 No significant change
hsa-miR-6855-5p 2.3206825 2.6920197 0.1185141 0.6612336 No significant change
hsa-miR-30d-3p 1.9658383 2.2380137 0.1185774 0.6612336 No significant change
hsa-miR-548g-3p 2.1365963 1.9277346 0.1202941 0.6612336 No significant change
hsa-miR-4632-5p –4.438452 1.6646651 0.1206023 0.6612336 No significant change
hsa-miR-223-5p 1.0326838 10.994597 0.1223615 0.6612336 No significant change
hsa-miR-148b-3p 0.8571842 9.1175856 0.1230929 0.6612336 No significant change
hsa-miR-511-5p –0.954287 7.6962227 0.1233912 0.6612336 No significant change
hsa-miR-3120-5p –1.569549 3.189544 0.1238989 0.6612336 No significant change
hsa-miR-6807-5p –1.68445 2.7656362 0.1258088 0.6612336 No significant change
hsa-miR-7706 –0.800976 8.1364183 0.1259873 0.6612336 No significant change
hsa-miR-6877-5p –0.97864 4.0346695 0.1281799 0.6612336 No significant change
hsa-miR-6867-5p –4.420387 1.6399348 0.128713 0.6612336 No significant change
hsa-miR-654-3p 1.4716482 4.058458 0.1292771 0.6612336 No significant change
hsa-miR-532-3p 1.3345266 3.0579425 0.1310935 0.6612336 No significant change
hsa-miR-139-5p –0.763961 8.7983053 0.1311084 0.6612336 No significant change
hsa-miR-150-5p –0.951721 4.5776261 0.1315027 0.6612336 No significant change
hsa-miR-29c-3p 1.590568 2.9374216 0.1321838 0.6612336 No significant change
hsa-miR-216b-5p 2.2373978 2.203677 0.1325936 0.6612336 No significant change
hsa-miR-182-5p 0.9661418 8.8897524 0.1333784 0.6612336 No significant change
hsa-miR-422a –1.078467 4.6298508 0.1338046 0.6612336 No significant change
hsa-miR-598-5p –2.666613 1.5735392 0.134677 0.6612336 No significant change
hsa-miR-5001-5p –2.551553 2.0369642 0.1370473 0.6620332 No significant change
hsa-miR-134-5p –0.980716 9.4215516 0.1373406 0.6620332 No significant change
hsa-miR-1284 2.4145406 2.1968535 0.1378813 0.6620332 No significant change
hsa-miR-3150a-3p –2.811773 1.5634735 0.1390433 0.6627395 No significant change
hsa-miR-363-3p 0.7073762 9.1043511 0.1413506 0.6688546 No significant change
hsa-miR-1228-5p –1.583718 5.6267219 0.1510184 0.6974406 No significant change
hsa-miR-451b 1.5556534 2.341655 0.1513468 0.6974406 No significant change
hsa-miR-4690-3p –1.585332 2.3122693 0.1546086 0.6974406 No significant change
hsa-miR-4492 1.8890749 2.6908575 0.1556186 0.6974406 No significant change
hsa-miR-22-5p 0.7113484 7.5008618 0.1564473 0.6974406 No significant change
hsa-miR-382-3p 2.6618706 1.8884254 0.1569376 0.6974406 No significant change
hsa-miR-1268a –1.344074 3.5173016 0.157215 0.6974406 No significant change
hsa-miR-130b-5p –1.349846 5.5368302 0.1573153 0.6974406 No significant change
hsa-miR-1908-5p –0.868376 5.3205733 0.1575061 0.6974406 No significant change
hsa-miR-1323 3.1754272 1.7499644 0.1587152 0.6974406 No significant change
hsa-miR-142-5p 0.9245943 10.746901 0.1591403 0.6974406 No significant change
hsa-miR-202-5p –2.148219 2.1091604 0.1611812 0.7016757 No significant change
hsa-miR-3614-5p 0.8235881 5.10239 0.1628295 0.7029907 No significant change
hsa-miR-4734 –2.388663 2.0593932 0.1636364 0.7029907 No significant change
hsa-miR-500a-3p 0.8190993 6.9227609 0.1671241 0.7088167 No significant change
hsa-miR-6837-3p 2.3338704 1.5337101 0.1671635 0.7088167 No significant change
hsa-miR-1251-5p 3.9176501 1.5341643 0.1714535 0.7155546 No significant change
hsa-miR-1303 –1.555532 2.6559909 0.1716289 0.7155546 No significant change
hsa-miR-6729-5p –1.590327 2.658534 0.1725684 0.7155546 No significant change
hsa-miR-3164 –1.40814 2.542441 0.1747991 0.7155546 No significant change
hsa-miR-4686 –2.712178 1.7671251 0.1754859 0.7155546 No significant change
hsa-miR-199a-5p –0.808327 5.143726 0.1766325 0.7155546 No significant change
hsa-let-7i-5p 0.6705203 13.732316 0.1767354 0.7155546 No significant change
hsa-miR-98-5p 1.0003412 5.4352618 0.1775189 0.7155546 No significant change
hsa-miR-148a-3p 0.9435646 16.290335 0.1788868 0.7166447 No significant change
hsa-miR-424-5p 1.8940264 2.2198714 0.1808803 0.7189678 No significant change
hsa-miR-4738-3p –0.927843 4.9421983 0.1816687 0.7189678 No significant change
hsa-miR-548av-5p 1.8025998 2.5786282 0.1845222 0.7226147 No significant change
hsa-miR-548k 1.8026604 2.5786282 0.1850914 0.7226147 No significant change
hsa-miR-10b-5p 0.9865763 13.490142 0.1869494 0.7226147 No significant change
hsa-miR-6894-5p –2.424955 1.6233922 0.1874297 0.7226147 No significant change
hsa-miR-502-3p 0.7905524 6.7211564 0.1881233 0.7226147 No significant change
hsa-miR-548d-5p 1.243827 2.8600041 0.1906509 0.728041 No significant change
hsa-miR-197-5p 2.5681216 1.5569566 0.193898 0.7361359 No significant change
hsa-miR-3177-3p –0.827688 4.3828417 0.2048054 0.7701355 No significant change
hsa-miR-483-3p –1.974456 2.2211816 0.2052122 0.7701355 No significant change
hsa-miR-4443 1.441188 2.0131336 0.209035 0.7769258 No significant change
hsa-miR-450b-5p 1.2773184 3.6255182 0.2094011 0.7769258 No significant change
hsa-miR-3944-5p –1.917286 1.6616247 0.2124654 0.7809496 No significant change
hsa-miR-378a-3p –0.693553 13.529209 0.2134582 0.7809496 No significant change
hsa-miR-1268b –1.253701 2.835488 0.2140735 0.7809496 No significant change
hsa-miR-1301-3p –0.672448 6.3965039 0.2153159 0.7811183 No significant change
hsa-miR-23b-3p 0.8317205 6.7190126 0.2166784 0.7817181 No significant change
hsa-let-7f-5p 0.9813044 12.771715 0.2203357 0.7827953 No significant change
hsa-miR-323a-3p 1.5421509 2.933777 0.2206817 0.7827953 No significant change
hsa-miR-146a-3p –1.471724 2.8336003 0.2229831 0.7827953 No significant change
hsa-miR-3615 –0.560017 11.59087 0.2231573 0.7827953 No significant change
hsa-miR-3653-3p 1.7884659 2.8943771 0.22665 0.7827953 No significant change
hsa-miR-4750-5p 2.1988462 2.2882648 0.2270104 0.7827953 No significant change
hsa-miR-30b-5p –1.173984 2.8123367 0.2281171 0.7827953 No significant change
hsa-miR-4685-3p 1.7002163 2.3598704 0.2284197 0.7827953 No significant change
hsa-miR-29a-3p 0.6296572 7.1061101 0.2285709 0.7827953 No significant change
hsa-miR-338-5p 0.9831061 5.1541294 0.2289646 0.7827953 No significant change
hsa-miR-409-5p –2.455029 1.8660302 0.2303949 0.7835825 No significant change
hsa-miR-6735-5p –1.113351 2.7252862 0.2358695 0.7980454 No significant change
hsa-miR-451a 0.692269 17.308079 0.2385771 0.8030457 No significant change
hsa-miR-543 –0.786827 5.8479538 0.2440816 0.8039067 No significant change
hsa-miR-320a –0.815342 17.450679 0.244879 0.8039067 No significant change
hsa-miR-9-5p –1.371276 3.587857 0.2459402 0.8039067 No significant change
hsa-miR-4669 –1.595144 5.8693776 0.2463495 0.8039067 No significant change
hsa-miR-423-5p 0.9427992 14.818582 0.247431 0.8039067 No significant change
hsa-miR-505-5p –1.271211 3.1783629 0.2483359 0.8039067 No significant change
hsa-miR-433-3p –0.847541 3.9645598 0.2494875 0.8039067 No significant change
hsa-miR-378f –0.711048 5.4020575 0.2506752 0.8039067 No significant change
hsa-miR-369-5p 1.4864754 2.4692721 0.2510632 0.8039067 No significant change
hsa-miR-2355-3p –1.15072 3.7739493 0.2511439 0.8039067 No significant change
hsa-miR-203a-3p –1.009401 2.9550279 0.2524344 0.8040958 No significant change
hsa-miR-324-5p –1.159804 2.7822215 0.2539581 0.8050225 No significant change
hsa-miR-6866-5p 1.21584 2.6771394 0.2586937 0.8156615 No significant change
hsa-miR-146b-5p –0.50629 10.058382 0.2598126 0.8156615 No significant change
hsa-miR-6850-5p –1.300932 3.5813908 0.2621724 0.8191319 No significant change
hsa-miR-6805-5p 1.685567 1.9214473 0.2660718 0.8253837 No significant change
hsa-miR-1288-3p 0.7195433 3.7822121 0.2698133 0.8253837 No significant change
hsa-miR-671-5p –1.32528 2.7635774 0.2698485 0.8253837 No significant change
hsa-miR-3198 1.1473064 2.8345948 0.2707223 0.8253837 No significant change
hsa-let-7g-5p 0.6845773 11.375567 0.2732324 0.8253837 No significant change
hsa-miR-15a-5p 1.1948987 3.6848885 0.2740772 0.8253837 No significant change
hsa-miR-125b-5p –0.732038 7.8426642 0.2741847 0.8253837 No significant change
hsa-miR-1304-3p 0.9043526 2.9166587 0.2780766 0.8253837 No significant change
hsa-miR-1307-5p 0.9063819 5.2243053 0.2796302 0.8253837 No significant change
hsa-miR-1304-5p 0.7762674 4.5305669 0.2802373 0.8253837 No significant change
hsa-let-7a-3p 0.9330917 4.8154346 0.2830936 0.8253837 No significant change
hsa-let-7c-5p 0.6875779 8.8167555 0.2861486 0.8253837 No significant change
hsa-miR-501-3p 0.5004423 8.0575092 0.2867648 0.8253837 No significant change
hsa-miR-4504 1.0350608 2.5326026 0.2872558 0.8253837 No significant change
hsa-miR-6740-5p –1.581123 1.7343998 0.2885572 0.8253837 No significant change
hsa-miR-548ah-3p –1.304342 3.3197506 0.2890754 0.8253837 No significant change
hsa-miR-548ah-5p 1.9294896 1.7038912 0.2893556 0.8253837 No significant change
hsa-miR-483-5p –0.930561 7.564909 0.2914031 0.8253837 No significant change
hsa-miR-660-5p 0.7075408 4.2882236 0.2914257 0.8253837 No significant change
hsa-miR-21-3p 0.9542321 2.4157215 0.2931474 0.8253837 No significant change
hsa-miR-3934-5p –1.212719 2.7002545 0.2933218 0.8253837 No significant change
hsa-miR-636 –0.964891 3.8563112 0.2935647 0.8253837 No significant change
hsa-miR-548o-3p 0.681933 6.0771291 0.293988 0.8253837 No significant change
hsa-miR-6847-5p –1.849893 1.800303 0.294509 0.8253837 No significant change
hsa-miR-548e-3p 1.6874698 2.8139597 0.2958437 0.825581 No significant change
hsa-miR-548aq-3p 1.0658174 2.5363606 0.2988553 0.8304362 No significant change
hsa-miR-548p –1.282776 2.5748882 0.3025163 0.8347429 No significant change
hsa-miR-224-5p –0.815762 5.4259038 0.3029618 0.8347429 No significant change
hsa-miR-6842-3p –0.54062 6.4181974 0.30662 0.8353266 No significant change
hsa-miR-6842-5p –1.10107 3.1350216 0.3067038 0.8353266 No significant change
hsa-miR-664a-5p –0.511649 7.5691025 0.3070113 0.8353266 No significant change
hsa-miR-29b-3p 0.9135712 3.3857084 0.3104169 0.8410881 No significant change
hsa-miR-4792 1.6281913 1.7670514 0.3132049 0.8451357 No significant change
hsa-miR-374b-5p 1.1494207 2.7976908 0.3161745 0.8482237 No significant change
hsa-miR-548ar-3p 2.0368642 1.7291385 0.3173662 0.8482237 No significant change
hsa-miR-101-3p 0.5091777 12.22281 0.3190473 0.8482237 No significant change
hsa-miR-19b-3p –0.513661 7.8691128 0.3195452 0.8482237 No significant change
hsa-miR-138-5p 1.746835 2.9430173 0.3222519 0.8519453 No significant change
hsa-miR-127-5p 1.3399919 1.9387115 0.3238221 0.8526446 No significant change
hsa-miR-6767-5p –1.215424 2.6648708 0.3260874 0.8551609 No significant change
hsa-miR-378g –0.675223 4.9405071 0.3296351 0.8602968 No significant change
hsa-miR-1291 –1.052421 3.0656529 0.3314369 0.8602968 No significant change
hsa-miR-340-5p 0.5921506 7.1447921 0.3319982 0.8602968 No significant change
hsa-miR-27b-3p 0.5606084 9.2327937 0.3354214 0.865732 No significant change
hsa-miR-133a-3p –1.010586 2.795073 0.3382356 0.8695584 No significant change
hsa-miR-3180-3p –0.846583 3.8598008 0.3411122 0.8701843 No significant change
hsa-miR-3180 –0.846582 3.8598008 0.3411442 0.8701843 No significant change
hsa-miR-548f-3p 1.0661786 3.2749608 0.3481526 0.8846056 No significant change
hsa-miR-454-3p 1.5722845 1.874925 0.3527671 0.8870067 No significant change
hsa-miR-3605-5p 0.8221827 3.5829053 0.3528511 0.8870067 No significant change
hsa-miR-3656 0.9575566 6.401001 0.3541452 0.8870067 No significant change
hsa-miR-200c-3p –0.712289 4.39608 0.3550301 0.8870067 No significant change
hsa-miR-4668-5p 1.392088 1.6240717 0.3558894 0.8870067 No significant change
hsa-miR-125a-3p 0.5399649 5.1715031 0.3592955 0.8870821 No significant change
hsa-miR-4449 1.5954564 1.9320423 0.3594572 0.8870821 No significant change
hsa-miR-409-3p –0.543216 9.7619462 0.3613628 0.8870821 No significant change
hsa-miR-191-5p –0.433838 10.619917 0.3616148 0.8870821 No significant change
hsa-miR-378b –0.880843 2.2021448 0.363823 0.8870821 No significant change
hsa-miR-7704 –0.984122 3.3957706 0.3641425 0.8870821 No significant change
hsa-miR-221-5p –1.002764 3.4954176 0.3673952 0.8870821 No significant change
hsa-miR-25-5p –0.493149 5.6091814 0.3679407 0.8870821 No significant change
hsa-miR-425-3p 0.541883 5.3104613 0.3681459 0.8870821 No significant change
hsa-miR-4533 –1.760573 2.1254106 0.3704092 0.8888605 No significant change
hsa-miR-933 –0.959165 2.3375305 0.3753003 0.8888605 No significant change
hsa-let-7a-5p 0.6497322 12.975814 0.3753405 0.8888605 No significant change
hsa-miR-4470 –0.892524 2.8122058 0.37695 0.8888605 No significant change
hsa-miR-2278 –1.766699 1.8778793 0.3770478 0.8888605 No significant change
hsa-miR-486-5p –0.457939 16.686046 0.3832073 0.8888605 No significant change
hsa-miR-3940-3p –1.408048 1.6608732 0.3832843 0.8888605 No significant change
hsa-miR-3187-3p –0.892137 2.5921695 0.3855747 0.8888605 No significant change
hsa-miR-4497 0.7392705 3.6014612 0.3870867 0.8888605 No significant change
hsa-miR-199b-5p 0.9836411 3.0620057 0.3880651 0.8888605 No significant change
hsa-miR-619-5p 0.7914885 3.6930173 0.3919101 0.8888605 No significant change
hsa-miR-486-3p –0.527163 9.2947109 0.3922085 0.8888605 No significant change
hsa-miR-877-5p 0.887142 2.7835525 0.3936675 0.8888605 No significant change
hsa-miR-26a-5p –0.438526 12.034981 0.3941645 0.8888605 No significant change
hsa-miR-130a-3p 0.7931839 3.452487 0.3962262 0.8888605 No significant change
hsa-miR-5189-3p –1.877746 1.5850335 0.3979336 0.8888605 No significant change
hsa-miR-219a-1-3p 0.6166556 3.9289159 0.3985645 0.8888605 No significant change
hsa-miR-3613-5p 1.0486812 3.4353781 0.3990407 0.8888605 No significant change
hsa-miR-6868-3p 1.5784115 1.83275 0.3993111 0.8888605 No significant change
hsa-miR-4326 0.5059312 4.695875 0.3996936 0.8888605 No significant change
hsa-miR-142-3p –0.539992 5.2761115 0.3999501 0.8888605 No significant change
hsa-miR-188-5p –1.772054 1.8330291 0.4003739 0.8888605 No significant change
hsa-miR-628-3p –0.815403 3.5364941 0.4020194 0.8888605 No significant change
hsa-miR-3163 –1.772486 1.7336399 0.4039195 0.8888605 No significant change
hsa-miR-6734-5p –0.785277 2.7896561 0.4039329 0.8888605 No significant change
hsa-miR-450a-2-3p 1.4317292 1.7596501 0.404995 0.8888605 No significant change
hsa-miR-181a-2-3p 0.5075986 5.4332687 0.4073637 0.8888605 No significant change
hsa-miR-95-3p 0.8544531 3.1519562 0.4083902 0.8888605 No significant change
hsa-miR-197-3p –0.449493 5.8276489 0.4095343 0.8888605 No significant change
hsa-let-7d-3p –0.56787 8.8293206 0.409823 0.8888605 No significant change
hsa-miR-1343-3p –0.946581 2.5133219 0.411081 0.8888605 No significant change
hsa-miR-28-5p –0.621388 4.630008 0.4174868 0.8997323 No significant change
hsa-miR-4746-5p –0.486839 4.7626153 0.4212221 0.9022778 No significant change
hsa-miR-766-5p –0.737694 3.3727211 0.422033 0.9022778 No significant change
hsa-miR-215-5p –0.480604 7.1161766 0.4249566 0.9022778 No significant change
hsa-miR-5584-5p –1.379773 1.7846595 0.425009 0.9022778 No significant change
hsa-let-7e-5p –0.46396 5.7291892 0.4267814 0.9022778 No significant change
hsa-miR-204-5p 1.0562679 3.1446046 0.4280874 0.9022778 No significant change
hsa-miR-505-3p 1.0115324 2.2007987 0.4311119 0.9022778 No significant change
hsa-miR-3960 –0.820323 3.0252496 0.4312514 0.9022778 No significant change
hsa-miR-769-5p 0.4131347 6.328532 0.434183 0.9022778 No significant change
hsa-miR-574-5p 0.5165305 4.4120608 0.4346184 0.9022778 No significant change
hsa-miR-4745-5p 1.1035172 1.8834507 0.4351774 0.9022778 No significant change
hsa-miR-6826-5p –1.549823 1.6679906 0.4374285 0.9022778 No significant change
hsa-miR-6873-3p –1.854291 1.8434449 0.4375316 0.9022778 No significant change
hsa-miR-1255a –1.492719 1.8463584 0.4389187 0.9022778 No significant change
hsa-miR-196a-5p 1.5897358 1.7211208 0.4393941 0.9022778 No significant change
hsa-miR-541-3p 1.6596473 1.537037 0.4433141 0.9048498 No significant change
hsa-miR-411-5p –1.076507 2.2087415 0.4435109 0.9048498 No significant change
hsa-miR-5010-3p –0.883236 2.7159418 0.4448037 0.9048498 No significant change
hsa-miR-627-5p –0.918525 3.6252789 0.4466178 0.9057188 No significant change
hsa-miR-1285-3p 0.3945564 7.1830884 0.4517263 0.9132424 No significant change
hsa-miR-190b –0.963908 2.677174 0.4545007 0.9144084 No significant change
hsa-miR-100-5p 0.4200413 9.5921916 0.4560086 0.9144084 No significant change
hsa-miR-361-5p 0.535013 4.8083803 0.4565041 0.9144084 No significant change
hsa-miR-5187-5p –0.867499 2.9017873 0.4591533 0.9148355 No significant change
hsa-miR-147b –0.589351 4.4667779 0.4623371 0.9148355 No significant change
hsa-miR-937-3p –0.974385 1.9353914 0.464301 0.9148355 No significant change
hsa-miR-6510-3p 1.0174261 1.7619231 0.4644156 0.9148355 No significant change
hsa-miR-939-5p –0.697256 4.0995899 0.4651244 0.9148355 No significant change
hsa-miR-378h –0.791617 2.3260691 0.4658731 0.9148355 No significant change
hsa-miR-217 1.3021498 1.9050108 0.4665241 0.9148355 No significant change
hsa-miR-7641 –0.468029 4.9366952 0.4690113 0.9154936 No significant change
hsa-miR-548av-3p 0.47114 6.252222 0.4733518 0.9154936 No significant change
hsa-miR-6741-5p 0.5949207 4.1714329 0.475308 0.9154936 No significant change
hsa-miR-654-5p –0.464514 4.8400168 0.4763995 0.9154936 No significant change
hsa-miR-200b-3p 0.7091144 5.0107698 0.4766057 0.9154936 No significant change
hsa-miR-1255b-5p –0.451304 5.6056901 0.4779232 0.9154936 No significant change
hsa-miR-491-5p 0.9313127 2.2497678 0.4789445 0.9154936 No significant change
hsa-miR-25-3p 0.3489736 14.27837 0.4791003 0.9154936 No significant change
hsa-miR-941 –0.409436 8.2614403 0.480218 0.9154936 No significant change
hsa-miR-1278 0.7481435 2.8317147 0.4808795 0.9154936 No significant change
hsa-miR-136-3p 1.1333558 2.080222 0.4856282 0.9218466 No significant change
hsa-miR-651-5p 0.8296741 2.8857899 0.4893942 0.9261983 No significant change
hsa-miR-2115-5p –0.654134 3.8568241 0.4947184 0.9261983 No significant change
hsa-miR-125b-1-3p –0.710074 2.5821846 0.4951871 0.9261983 No significant change
hsa-miR-432-5p 0.519459 5.7732312 0.4973734 0.9261983 No significant change
hsa-miR-370-3p –0.449291 8.5231489 0.4995561 0.9261983 No significant change
hsa-miR-30e-3p 0.4303092 6.2012746 0.5015477 0.9261983 No significant change
hsa-miR-4664-3p 0.6964219 2.9212932 0.5026916 0.9261983 No significant change
hsa-miR-199b-3p 0.3983955 7.7412834 0.5028777 0.9261983 No significant change
hsa-miR-199a-3p 0.3983957 7.7412834 0.5029159 0.9261983 No significant change
hsa-miR-3135a 0.84727 2.265136 0.503214 0.9261983 No significant change
hsa-miR-200b-5p –1.018736 2.4345379 0.5041833 0.9261983 No significant change
hsa-miR-485-5p –0.452521 5.3178514 0.5057817 0.9261983 No significant change
hsa-miR-7854-3p 0.5668372 4.1261832 0.5063595 0.9261983 No significant change
hsa-miR-6500-3p 1.8457938 1.5789995 0.5102098 0.9267524 No significant change
hsa-miR-342-5p –0.371101 7.9757891 0.5117793 0.9267524 No significant change
hsa-miR-4429 –0.486907 6.5545003 0.5128256 0.9267524 No significant change
hsa-miR-106b-3p 0.2971658 9.6962724 0.5135598 0.9267524 No significant change
hsa-miR-1468-5p –0.43149 4.4314904 0.5138861 0.9267524 No significant change
hsa-miR-192-5p –0.389268 10.907 0.5151779 0.9267524 No significant change
hsa-miR-30b-3p –0.748655 2.2392432 0.5199714 0.9326946 No significant change
hsa-miR-200a-3p 0.6084755 6.0034314 0.5225511 0.9326946 No significant change
hsa-miR-99b-3p 0.4425954 5.2962311 0.5242053 0.9326946 No significant change
hsa-miR-125b-2-3p –0.495967 4.2076181 0.5252565 0.9326946 No significant change
hsa-miR-128-3p –0.413722 11.383902 0.5262359 0.9326946 No significant change
hsa-miR-92b-3p –0.432807 5.4786538 0.527051 0.9326946 No significant change
hsa-miR-143-5p 0.6269091 3.0870524 0.5297608 0.9335995 No significant change
hsa-miR-3911 0.9320473 2.7415764 0.5304218 0.9335995 No significant change
hsa-miR-103a-3p 0.3054391 10.354731 0.532489 0.933819 No significant change
hsa-miR-30c-2-3p 0.8425485 2.1752655 0.5354484 0.933819 No significant change
hsa-miR-495-3p 0.5291727 5.4675532 0.5364552 0.933819 No significant change
hsa-miR-26a-2-3p 1.5198874 1.6029344 0.537599 0.933819 No significant change
hsa-miR-126-3p –0.307273 12.413148 0.5394743 0.933819 No significant change
hsa-miR-3682-3p 0.8143584 2.1060439 0.5407325 0.933819 No significant change
hsa-miR-4448 –0.876161 1.5648166 0.5432524 0.933819 No significant change
hsa-miR-132-5p 0.4250566 4.3840081 0.5436233 0.933819 No significant change
hsa-miR-93-3p –0.591315 2.8480514 0.5445439 0.933819 No significant change
hsa-miR-32-3p 1.4328408 1.761357 0.5497012 0.933819 No significant change
hsa-miR-20a-5p 0.3778838 7.2058472 0.5502776 0.933819 No significant change
hsa-let-7i-3p –1.322239 1.8790777 0.5505762 0.933819 No significant change
hsa-miR-329-3p 1.0060924 1.8428753 0.5517286 0.933819 No significant change
hsa-miR-493-5p 1.0914151 2.0729394 0.5527974 0.933819 No significant change
hsa-miR-6878-5p –0.96207 1.8275946 0.5547283 0.933819 No significant change
hsa-miR-151a-3p –0.27039 15.042613 0.5547518 0.933819 No significant change
hsa-miR-92a-1-5p –0.931699 2.2804479 0.5563017 0.933819 No significant change
hsa-miR-4660 0.9567759 2.2283856 0.5576035 0.933819 No significant change
hsa-miR-4753-5p 0.8188679 2.3354297 0.5577173 0.933819 No significant change
hsa-miR-340-3p –0.525408 4.2639904 0.5619548 0.9344595 No significant change
hsa-miR-34c-5p –0.909724 1.6655184 0.5621801 0.9344595 No significant change
hsa-miR-10b-3p 0.4665191 4.8883603 0.5623929 0.9344595 No significant change
hsa-miR-4661-5p 0.5212449 3.0750091 0.5707537 0.9441812 No significant change
hsa-miR-32-5p 0.5611341 3.1275875 0.5711357 0.9441812 No significant change
hsa-miR-452-5p –0.358746 6.0219301 0.5733542 0.9444801 No significant change
hsa-miR-548j-3p –0.753882 2.6190697 0.5742183 0.9444801 No significant change
hsa-miR-148b-5p –0.665622 2.4664456 0.5756555 0.9444801 No significant change
hsa-miR-1180-3p –0.27482 9.0281703 0.5774878 0.9448464 No significant change
hsa-miR-17-3p –0.975126 1.8903205 0.5787727 0.9448464 No significant change
hsa-miR-3127-5p 0.5802173 2.6355728 0.5831993 0.9496986 No significant change
hsa-miR-195-5p 0.7432878 2.5018688 0.5882275 0.9555039 No significant change
hsa-miR-6515-5p 0.480945 3.6303755 0.5977744 0.9686022 No significant change
hsa-miR-1294 0.3463651 4.9323371 0.6005949 0.9707635 No significant change
hsa-miR-6514-5p 0.6198655 2.4006283 0.6028692 0.9720336 No significant change
hsa-miR-7850-5p –1.024476 2.1457357 0.604671 0.9725373 No significant change
hsa-miR-132-3p –0.523232 3.0640587 0.6091789 0.9773803 No significant change
hsa-miR-5581-3p –1.118694 1.7023392 0.6108762 0.9777013 No significant change
hsa-miR-6786-3p –0.820001 1.8540161 0.6153652 0.9824779 No significant change
hsa-miR-24-1-5p –0.588733 2.4993969 0.617275 0.9831234 No significant change
hsa-miR-296-3p 0.6198184 2.7034605 0.6200719 0.9851751 No significant change
hsa-miR-598-3p 0.6728758 2.2566853 0.6236678 0.9884833 No significant change
hsa-miR-4646-5p –0.540847 2.2912729 0.6262776 0.9902161 No significant change
hsa-miR-4440 –0.590112 2.2793566 0.6389004 0.998528 No significant change
hsa-miR-1273 h-5p –0.423921 3.790786 0.6391411 0.998528 No significant change
hsa-miR-576-3p –0.237687 8.7340672 0.6404048 0.998528 No significant change
hsa-miR-4516 0.5384799 1.8270786 0.6444029 0.998528 No significant change
hsa-miR-28-3p –0.216384 9.2362065 0.6463092 0.998528 No significant change
hsa-miR-140-5p 0.3691516 4.3450804 0.6475597 0.998528 No significant change
hsa-miR-4781-3p –0.766654 1.9600532 0.6478883 0.998528 No significant change
hsa-miR-320b –0.318763 13.64376 0.6490834 0.998528 No significant change
hsa-miR-4726-5p –1.115035 1.9321852 0.6506376 0.998528 No significant change
hsa-miR-615-3p 0.4995548 5.2957599 0.6513457 0.998528 No significant change
hsa-miR-4437 1.1238567 1.7013377 0.6521391 0.998528 No significant change
hsa-miR-185-3p –0.275583 5.4041765 0.6547088 0.998528 No significant change
hsa-miR-1250-5p –0.460275 3.1292287 0.6572677 0.998528 No significant change
hsa-miR-532-5p 0.2024342 10.463505 0.6572883 0.998528 No significant change
hsa-miR-3620-5p 0.5327481 2.1730518 0.6581288 0.998528 No significant change
hsa-miR-6862-5p 0.7339734 1.6578542 0.6583556 0.998528 No significant change
hsa-miR-339-5p 0.3599348 3.5420369 0.6601304 0.998528 No significant change
hsa-miR-193b-3p 0.8355395 1.8348219 0.6603539 0.998528 No significant change
hsa-miR-24-3p 0.2119127 12.483615 0.6619422 0.998528 No significant change
hsa-miR-361-3p 0.1967387 8.9290252 0.6630333 0.998528 No significant change
hsa-miR-4487 –1.150809 1.5697953 0.6636738 0.998528 No significant change
hsa-miR-548 am-3p 0.5151226 2.9610665 0.6672588 0.998528 No significant change
hsa-miR-335-3p 0.4041049 3.4163132 0.6699615 0.998528 No significant change
hsa-miR-484 0.229637 8.2303032 0.6701036 0.998528 No significant change
hsa-miR-320d 0.3203703 8.7720833 0.6708687 0.998528 No significant change
hsa-let-7d-5p 0.2711084 9.2664515 0.6716954 0.998528 No significant change
hsa-miR-196b-5p 0.4329791 2.7583364 0.6767531 0.998528 No significant change
hsa-miR-27b-5p 0.558564 2.7912571 0.6788834 0.998528 No significant change
hsa-miR-1287-5p 0.3675621 3.7248861 0.6808377 0.998528 No significant change
hsa-miR-92a-3p –0.252647 13.837765 0.6825184 0.998528 No significant change
hsa-miR-1273c –0.552522 2.4781665 0.6829609 0.998528 No significant change
hsa-miR-22-3p –0.181389 12.447027 0.6853361 0.998528 No significant change
hsa-miR-766-3p 0.5614117 2.0406306 0.6855555 0.998528 No significant change
hsa-miR-6503-3p –0.300207 3.7972393 0.6860794 0.998528 No significant change
hsa-miR-1285-5p 0.9950226 1.6454397 0.6864892 0.998528 No significant change
hsa-miR-181c-3p 0.4292827 2.6901574 0.6865836 0.998528 No significant change
hsa-miR-4467 0.593421 2.5365632 0.6902773 1 No significant change
hsa-miR-642a-3p –0.475432 3.218189 0.6940372 1 No significant change
hsa-miR-3605-3p –0.659132 2.4770723 0.6959227 1 No significant change
hsa-miR-3120-3p –0.325219 3.1488579 0.6986896 1 No significant change
hsa-miR-1273d –0.390783 2.8524222 0.7006583 1 No significant change
hsa-miR-222-3p 0.2087115 8.733134 0.7030174 1 No significant change
hsa-miR-181b-5p 0.2230656 7.8256168 0.7093748 1 No significant change
hsa-miR-4508 0.2850097 10.424708 0.7104169 1 No significant change
hsa-miR-548u –0.564302 1.9814485 0.7105777 1 No significant change
hsa-miR-99b-5p 0.1950643 9.4466971 0.7123201 1 No significant change
hsa-miR-1261 0.6235688 1.6884782 0.7126422 1 No significant change
hsa-miR-381-3p –0.230675 5.2889809 0.7160037 1 No significant change
hsa-miR-504-5p 0.6595251 1.840255 0.7163579 1 No significant change
hsa-let-7f-1-3p –0.456075 2.6797566 0.7247934 1 No significant change
hsa-miR-18a-3p –0.443758 3.3336327 0.7260352 1 No significant change
hsa-miR-618 0.4127825 2.9891759 0.726983 1 No significant change
hsa-miR-3138 –0.74913 1.8268181 0.7309819 1 No significant change
hsa-miR-328-3p –0.172131 6.7513695 0.7320352 1 No significant change
hsa-miR-6806-3p 0.3706707 3.2665815 0.7329487 1 No significant change
hsa-miR-144-3p –0.190136 5.9284579 0.7339561 1 No significant change
hsa-miR-1270 0.520736 2.0035059 0.7360031 1 No significant change
hsa-miR-4659b-3p –0.917316 1.5945608 0.736333 1 No significant change
hsa-miR-514a-3p 0.6644575 1.7627173 0.7364687 1 No significant change
hsa-miR-4654 –0.639538 2.2814597 0.7428239 1 No significant change
hsa-miR-7976 0.2280299 4.0552938 0.7431302 1 No significant change
hsa-miR-873-3p 0.2994708 4.2232817 0.7461015 1 No significant change
hsa-miR-424-3p 0.1711323 7.213438 0.7466318 1 No significant change
hsa-miR-942-3p –0.57066 2.2759455 0.7520299 1 No significant change
hsa-miR-214-5p 0.431421 2.5325743 0.7535177 1 No significant change
hsa-miR-610 –0.383532 2.7463828 0.75393 1 No significant change
hsa-miR-186-5p –0.146939 10.210479 0.7553595 1 No significant change
hsa-miR-629-5p 0.1695189 11.264791 0.7570134 1 No significant change
hsa-miR-205-5p –0.455482 2.2163267 0.7575052 1 No significant change
hsa-miR-1538 –0.377836 2.4773178 0.7581975 1 No significant change
hsa-miR-4742-3p –0.574425 1.9656415 0.7616509 1 No significant change
hsa-miR-152-3p –0.174723 7.8755973 0.7639043 1 No significant change
hsa-miR-1260b –0.231988 4.0258788 0.764817 1 No significant change
hsa-miR-191-3p –0.25857 3.61125 0.7662529 1 No significant change
hsa-miR-1290 0.1721372 8.2902743 0.7672001 1 No significant change
hsa-miR-3158-3p –0.150834 10.637015 0.7672692 1 No significant change
hsa-miR-128-1-5p 0.5000403 2.0766789 0.7682668 1 No significant change
hsa-miR-4286 0.5162647 1.8443175 0.7748452 1 No significant change
hsa-miR-335-5p 0.1935597 5.8316106 0.7760272 1 No significant change
hsa-miR-210-3p –0.196257 5.3267414 0.7767807 1 No significant change
hsa-miR-26b-5p 0.1781976 7.6648112 0.779013 1 No significant change
hsa-miR-7-5p 0.1337923 11.093445 0.7829657 1 No significant change
hsa-miR-3691-5p 0.379601 2.1907458 0.7857847 1 No significant change
hsa-miR-99a-5p –0.150372 13.569867 0.7888686 1 No significant change
hsa-miR-183-5p 0.1712702 8.4813048 0.7917523 1 No significant change
hsa-miR-6821-5p –0.492681 1.8236572 0.7997148 1 No significant change
hsa-miR-6750-5p –0.256561 2.9791013 0.8027427 1 No significant change
hsa-miR-18a-5p 0.5312005 1.9085935 0.8039216 1 No significant change
hsa-miR-3679-5p –0.50048 1.9657891 0.8070612 1 No significant change
hsa-miR-345-5p –0.126043 7.1103577 0.8075758 1 No significant change
hsa-miR-155-5p 0.1897688 5.3261139 0.8080494 1 No significant change
hsa-miR-659-5p –0.176787 4.4825036 0.8089872 1 No significant change
hsa-miR-4772-5p –0.384025 2.2172399 0.8123832 1 No significant change
hsa-miR-576-5p –0.317823 3.4446128 0.8160607 1 No significant change
hsa-miR-6829-5p 0.6573233 1.6803528 0.8162284 1 No significant change
hsa-miR-5189-5p –0.264712 3.6969312 0.8197824 1 No significant change
hsa-miR-4797-3p 0.4977217 1.5706456 0.820753 1 No significant change
hsa-miR-378d 0.1598743 6.4744816 0.8221808 1 No significant change
hsa-miR-151a-5p –0.18985 3.7719524 0.8231726 1 No significant change
hsa-miR-320c –0.159486 10.917939 0.8235317 1 No significant change
hsa-miR-106b-5p –0.138543 5.3341027 0.824224 1 No significant change
hsa-miR-379-5p 0.222008 4.5838907 0.8261351 1 No significant change
hsa-miR-20b-5p –0.13832 4.8649519 0.8270214 1 No significant change
hsa-miR-1273f 0.2724247 2.587597 0.8292921 1 No significant change
hsa-let-7b-5p –0.10784 13.325142 0.8299265 1 No significant change
hsa-miR-3140-3p –0.352147 2.0932723 0.8308651 1 No significant change
hsa-miR-145-5p 0.1794492 4.3511282 0.8321114 1 No significant change
hsa-miR-548ap-5p 0.2600483 2.013502 0.8325445 1 No significant change
hsa-miR-181a-3p –0.210737 3.0554496 0.8333932 1 No significant change
hsa-miR-378i –0.12108 8.7999496 0.8356999 1 No significant change
hsa-miR-3199 –0.464373 1.9923827 0.8375008 1 No significant change
hsa-miR-3127-3p –0.622897 1.8005486 0.839874 1 No significant change
hsa-miR-429 –0.349153 2.5510879 0.8453863 1 No significant change
hsa-miR-374a-5p 0.2264504 3.08939 0.8493638 1 No significant change
hsa-miR-382-5p 0.1095212 6.9416982 0.8513419 1 No significant change
hsa-miR-6761-5p 0.623679 1.5495384 0.851564 1 No significant change
hsa-miR-6875-5p 0.5211668 1.9400319 0.8515798 1 No significant change
hsa-miR-423-3p –0.081611 11.872407 0.8551171 1 No significant change
hsa-miR-6087 0.5822617 1.6075862 0.8554071 1 No significant change
hsa-miR-6882-5p 0.5191495 1.5787126 0.8563317 1 No significant change
hsa-miR-3196 –0.549764 1.5610905 0.8597365 1 No significant change
hsa-miR-96-5p 0.2017521 3.5027927 0.8604698 1 No significant change
hsa-miR-339-3p –0.101156 7.3890387 0.8610593 1 No significant change
hsa-miR-30e-5p –0.080126 9.4771337 0.8619278 1 No significant change
hsa-miR-23a-5p –0.152271 3.5446331 0.8653128 1 No significant change
hsa-miR-4657 0.2977558 2.2053827 0.8655121 1 No significant change
hsa-miR-4741 –0.333654 1.7772274 0.8678381 1 No significant change
hsa-miR-574-3p –0.137952 4.5991981 0.8685275 1 No significant change
hsa-miR-493-3p –0.1203 5.6154489 0.869264 1 No significant change
hsa-miR-455-5p –0.157462 4.0515121 0.8712733 1 No significant change
hsa-miR-4747-5p –0.661522 1.7532446 0.8736084 1 No significant change
hsa-miR-3179 0.6739758 1.5372134 0.8739323 1 No significant change
hsa-miR-374a-3p 0.3015378 1.7177352 0.8780622 1 No significant change
hsa-miR-378a-5p 0.2966664 2.4421476 0.8791134 1 No significant change
hsa-miR-760 –0.093872 5.9505312 0.8803434 1 No significant change
hsa-miR-4639-5p –0.473142 1.6020946 0.8813641 1 No significant change
hsa-miR-3176 0.1416603 2.633019 0.8829953 1 No significant change
hsa-miR-3124-5p –0.173389 3.1259251 0.8844519 1 No significant change
hsa-miR-625-3p –0.107002 6.3989775 0.8845203 1 No significant change
hsa-miR-3150b-3p –0.09592 5.0180538 0.8850272 1 No significant change
hsa-miR-4466 –0.251913 1.8275556 0.8857244 1 No significant change
hsa-miR-106a-5p 0.1404881 3.9283878 0.8875824 1 No significant change
hsa-miR-24-2-5p –0.076083 5.9103213 0.8884291 1 No significant change
hsa-miR-1254 0.1420986 3.1668722 0.889156 1 No significant change
hsa-miR-10a-5p –0.092127 11.262034 0.8892013 1 No significant change
hsa-miR-17-5p –0.078709 6.5255191 0.8896858 1 No significant change
hsa-miR-330-5p –0.082862 5.9135167 0.889776 1 No significant change
hsa-miR-3074-5p 0.2956317 1.9012105 0.8900359 1 No significant change
hsa-miR-136-5p 0.1804324 3.1208797 0.8961827 1 No significant change
hsa-miR-324-3p –0.133559 3.0058811 0.8999955 1 No significant change
hsa-miR-550a-3-5p 0.0642257 6.5796374 0.9014026 1 No significant change
hsa-miR-26b-3p –0.307955 2.0010125 0.9021122 1 No significant change
hsa-miR-4498 –0.334558 1.7491314 0.9061182 1 No significant change
hsa-miR-331-3p 0.2704766 2.0127679 0.9077998 1 No significant change
hsa-miR-579-5p –0.245458 2.6388852 0.9080854 1 No significant change
hsa-miR-195-3p 0.1067741 4.2095303 0.9104302 1 No significant change
hsa-miR-365b-5p 0.2707665 1.9595275 0.9105269 1 No significant change
hsa-miR-3909 –0.307887 1.9703924 0.9147102 1 No significant change
hsa-miR-146a-5p –0.049813 12.137534 0.915202 1 No significant change
hsa-miR-3064-5p 0.2325321 2.1106126 0.9163336 1 No significant change
hsa-miR-625-5p 0.3627439 1.8957884 0.9165356 1 No significant change
hsa-miR-499a-5p 0.0695846 4.7989112 0.9183591 1 No significant change
hsa-miR-548q –0.43038 1.8164982 0.9198613 1 No significant change
hsa-miR-5009-5p –0.085235 3.9249393 0.9211642 1 No significant change
hsa-miR-4473 0.1809776 1.9647736 0.9229154 1 No significant change
hsa-miR-616-3p –0.148683 2.3564493 0.9251134 1 No significant change
hsa-miR-1260a 0.1245625 3.3867094 0.9268289 1 No significant change
hsa-miR-127-3p –0.057308 7.7098832 0.9280109 1 No significant change
hsa-miR-10a-3p 0.201966 2.4165085 0.9285191 1 No significant change
hsa-miR-942-5p –0.050538 5.7554159 0.9304011 1 No significant change
hsa-miR-3150a-5p –0.248033 2.1840462 0.9333478 1 No significant change
hsa-miR-5010-5p –0.189689 2.350888 0.9345151 1 No significant change
hsa-miR-19a-3p 0.0668718 5.5469139 0.9349623 1 No significant change
hsa-miR-4647 0.1021053 3.7580773 0.9361456 1 No significant change
hsa-miR-30c-5p –0.0508 6.8428024 0.937609 1 No significant change
hsa-miR-221-3p 0.0399429 8.2407437 0.9392216 1 No significant change
hsa-miR-30d-5p –0.03734 12.788792 0.9417539 1 No significant change
hsa-miR-200a-5p 0.2100791 2.914263 0.9417815 1 No significant change
hsa-miR-4732-5p –0.049304 6.2671787 0.9429188 1 No significant change
hsa-miR-372-3p 0.1224369 3.8880673 0.9438989 1 No significant change
hsa-miR-93-5p –0.03724 7.579707 0.9448046 1 No significant change
hsa-miR-550a-5p 0.0395062 6.1547169 0.9474948 1 No significant change
hsa-miR-21-5p –0.030495 11.73524 0.947789 1 No significant change
hsa-miR-342-3p 0.0479521 4.6590461 0.9550105 1 No significant change
hsa-miR-23b-5p –0.068261 3.8807056 0.95638 1 No significant change
hsa-miR-3190-3p 0.1326734 2.9480806 0.9571401 1 No significant change
hsa-miR-363-5p 0.1331389 2.9921604 0.9584856 1 No significant change
hsa-miR-874-3p –0.074864 3.6263968 0.9593245 1 No significant change
hsa-miR-4755-3p –0.080479 3.1370278 0.9604028 1 No significant change
hsa-miR-1-3p –0.036418 7.1798175 0.9632119 1 No significant change
hsa-miR-126-5p –0.065305 4.0084407 0.9647803 1 No significant change
hsa-miR-652-3p –0.029345 5.9122246 0.9663523 1 No significant change
hsa-miR-129-5p –0.028294 6.9821323 0.9675328 1 No significant change
hsa-miR-16-2-3p –0.027523 8.811907 0.9683208 1 No significant change
hsa-miR-1306-3p –0.031442 5.7717178 0.970366 1 No significant change
hsa-miR-92b-5p –0.04648 4.4099962 0.9724563 1 No significant change
hsa-miR-194-5p 0.022113 7.9164417 0.9727306 1 No significant change
hsa-let-7b-3p 0.0437895 3.4838939 0.9734918 1 No significant change
hsa-miR-130b-3p –0.025812 4.1504386 0.9771869 1 No significant change
hsa-miR-584-5p –0.015047 9.1985501 0.9774408 1 No significant change
hsa-miR-151b 0.0243652 4.2112358 0.9787314 1 No significant change
hsa-miR-181a-5p –0.010282 10.939446 0.9820032 1 No significant change
hsa-miR-6852-5p 0.018814 4.5947672 0.9862641 1 No significant change
hsa-miR-425-5p 0.0062513 8.9639875 0.9896049 1 No significant change
hsa-miR-181d-5p –0.008651 5.0182536 1 1 No significant change
hsa-miR-516b-5p –0.102628 2.8190711 1 1 No significant change
hsa-miR-641 –0.097843 2.2703868 1 1 No significant change
hsa-miR-1273a –0.342187 1.5409936 1 1 No significant change
hsa-miR-548j-5p 0.2238124 1.9356194 1 1 No significant change
hsa-miR-548az-5p 0.132175 2.2329598 1 1 No significant change
hsa-miR-371b-5p 0.3474716 1.6005097 1 1 No significant change
hsa-miR-6716-3p 0.3315585 1.5923398 1 1 No significant change
hsa-miR-4306 –0.328855 1.5904479 1 1 No significant change
hsa-miR-6839-5p 0.2973405 1.6928111 1 1 No significant change
hsa-miR-6774-5p –0.253602 1.5400938 1 1 No significant change
hsa-miR-6818-5p –0.234782 1.882618 1 1 No significant change
hsa-miR-6781-5p 0.2234265 1.5361868 1 1 No significant change
hsa-miR-4800-5p 0.2154358 2.0145414 1 1 No significant change
hsa-miR-365a-5p 0.1827695 1.7779599 1 1 No significant change
hsa-miR-500b-3p 0.1643585 2.0396018 1 1 No significant change
hsa-miR-581 0.1637864 1.9969262 1 1 No significant change
hsa-miR-6501-5p 0.1422351 1.7067184 1 1 No significant change
hsa-miR-494-3p –0.131872 1.772495 1 1 No significant change
hsa-miR-556-5p –0.13052 1.7384358 1 1 No significant change
hsa-miR-6780a-5p 0.1235197 1.982604 1 1 No significant change
hsa-miR-6815-5p –0.074996 2.4337051 1 1 No significant change
hsa-miR-5096 0.0728714 2.3294423 1 1 No significant change
hsa-miR-5003-3p –0.070553 2.0370795 1 1 No significant change
hsa-miR-4724-5p 0.0690548 1.7048819 1 1 No significant change
hsa-miR-431-5p 0.0633666 2.2752355 1 1 No significant change
hsa-miR-664b-5p –0.062252 2.0530893 1 1 No significant change
hsa-miR-3122 –0.060705 1.7377483 1 1 No significant change
hsa-miR-3690 0.0440439 3.0985568 1 1 No significant change
hsa-miR-30c-1-3p –0.037941 1.8684588 1 1 No significant change
hsa-miR-3675-5p 0.0377325 1.9123711 1 1 No significant change
hsa-miR-6733-5p –0.024292 1.5948618 1 1 No significant change
hsa-miR-4433b-3p –0.014877 4.8281722 1 1 No significant change
hsa-miR-412-5p –0.005298 2.4102135 1 1 No significant change
hsa-miR-29c-5p –0.001197 2.7045493 1 1 No significant change
hsa-miR-144-5p –0.000254 4.0263451 1 1 No significant change
hsa-miR-375 –2.907928 10.621211 4.83E-08 3.16E-05 Down
hsa-miR-885-3p –5.273985 2.4001832 0.0012326 0.2345272 Down
hsa-miR-122-5p –2.159821 17.22628 0.0025547 0.2345272 Down
hsa-miR-4433b-5p –2.274328 4.5227663 0.0026641 0.2345272 Down
hsa-miR-4446-3p –1.711338 4.6900748 0.0070462 0.2367778 Down
hsa-miR-885-5p –4.134922 2.5015312 0.0084043 0.2494538 Down
hsa-miR-362-5p –4.25044 2.1184963 0.0100574 0.2623126 Down
hsa-miR-150-3p –1.462253 6.4066843 0.010493 0.2623126 Down
hsa-miR-3173-5p –2.254604 2.6784423 0.0169241 0.3683817 Down
hsa-miR-139-3p –1.429749 6.6299538 0.0182671 0.3847879 Down
hsa-miR-378e –2.947571 3.6008184 0.0217626 0.4111132 Down
hsa-miR-193b-5p –1.525996 7.0763764 0.0220352 0.4111132 Down
hsa-miR-4435 –2.038539 2.5392622 0.0239251 0.4123441 Down
hsa-miR-3191-3p –3.112364 2.2600313 0.0324487 0.4546377 Down
hsa-miR-4665-5p –1.786367 4.0103789 0.0351945 0.4787914 Down
hsa-miR-1249-3p –4.366691 1.6361465 0.0367761 0.4900979 Down
hsa-miR-1299 –2.231941 8.5118765 0.0377554 0.4914672 Down
hsa-miR-6884-5p –1.81515 4.2670509 0.0391367 0.4914672 Down
hsa-miR-1247-5p –4.90665 1.8784532 0.0407562 0.5021471 Down
hsa-miR-4732-3p –1.108072 6.6087268 0.04229 0.5113961 Down
hsa-miR-320e –1.994268 5.4474059 0.0455123 0.5261696 Down
hsa-miR-146b-3p –1.406413 4.6172767 0.046692 0.5261696 Down
hsa-miR-6511a-5p –3.261756 2.1336766 0.0467348 0.5261696 Down
hsa-miR-193a-5p –1.202926 11.155122 0.0489339 0.5415905 Down
Details are in the caption following the image
Details are in the caption following the image
Details are in the caption following the image
Details are in the caption following the image

3.2. Construction of miRNA-mRNA Network

Next, we analyzed the potential targets of the three differentially expressed serum microvesicles miRNAs by miRWalk, and found a total of 593 genes may be co-regulated by at least two of the three miRNAs, of which 192 genes were co-targeted by hsa-miR-15b-5p and hsa-miR-16-5p, 250 genes were co-targeted by hsa-miR-15b-5p and hsa-miR-184, 92 genes were co-targeted by hsa-miR-16-5p and hsa-miR-184, and 59 genes were co-targeted by the three miRNAs (Figures 2(a) and 2(b) and Table 2). Given that miRNA negatively regulates the expressions of its targets, we further intersected the 593 prediction genes with the downregulated-expressed genes of PBMCs of IS patients from GSE22255 [26], and obtained 25 genes (Figure 2(c)). The expression of the 25 intersected genes was shown in Figure 2(d). Then, the network containing 3 miRNAs and 25 mRNAs was visualized by the “ggallouvial” package of R software and was shown in Figure 3.

Details are in the caption following the image
Details are in the caption following the image
Details are in the caption following the image
Details are in the caption following the image
2. Target genes of the three miRNAs.
Potential targets of hsa-miR-15b-5p Potential targets of hsa-miR-16-5p Potential targets of hsa-miR-184 Potential targets of hsa-miR-15b-5p AND hsa-miR-16-5p NOT hsa-miR-184 Potential targets of hsa-miR-15b-5p AND hsa-miR-184 NOT hsa-miR-16-5p Potential targets of hsa-miR-16-5p AND hsa-miR-184 NOT hsa-miR-15b-5p Potential targets of hsa-miR-15b-5p AND hsa-miR-16-5p AND hsa-miR-184
CPD EXT1 STRADA STAMBPL1 TASOR CCDC80 RAB30
USP14 RNF157 BCAT2 DCAF12L2 ELP2 LIPH BCL11A
SETD5 PDLIM7 STX6 CTSC PI4K2A OPN3 ZMAT3
SESN1 NCOA6 TLCD3A RCC2 FAM204A PHKG2 NEK10
TTPAL NCS1 FTCD MCRIP1 CYB561D1 SLC4A8 PPP2R2B
GLS2 UBE2J1 CHST14 GFI1B NOP9 XRRA1 CDRT1
GALK2 PHACTR4 MAP4K4 CUL3 CTDP1 IST1 BEST3
DCLRE1C PPM1D ERVV-1 RAB44 TSHZ2 ZFAND5 MTA3
CRADD TRIP12 SYNE3 UBE2V1 RAI14 DIXDC1 MPI
TSPYL5 FBXW7 ZNF707 FRMD6 RBBP4 SURF4 TMEM106A
B3GAT1 RPS14 DLX1 CLOCK CBX5 RAD9B TMCC3
SNRK DHX33 RNF38 RAB3IP TBCD ZRANB3 SNX19
PRAMEF8 TMEM143 M1AP STT3A STK24 RUBCNL PARP15
AKR1B15 DEPDC1B HSPA12A PDK1 JAKMIP3 CCL4L2 TFRC
MBP IRAK3 MTMR10 HPCAL4 SSBP2 RXRA DLK1
VASH1 MRTFA SLC16A3 TTC1 NFATC2 ACP2 TBC1D7
OTUB1 DDX6 EFCAB14 TLE4 SHTN1 CYSLTR2 GPR63
SMURF1 IKZF3 JOSD1 GOT2 CDH19 EZH1 SON
ODF2L VPS50 RAB21 USP49 DNAJC10 C1orf21 SLC9A7
PTPRJ SLC4A7 RETSAT ADD1 CSNK1A1 HNRNPDL BTBD9
SORD KIF18B SHQ1 CALML4 ORAI2 CCDC115 XKR4
VPS9D1 GPR161 QRSL1 RCL1 SCIMP NFKBID NOPCHAP1
CORIN CD274 CYCS NADK2 IGSF9B GNB1L ZNF597
HSPA13 SOCS2 MDM1 CPEB1 AMOTL2 SLC30A7 PANK2
KRR1 MCU UBR4 POLH CEP43 CREB1 MOB1B
IL3 PGR SYT13 TRERF1 ARFGAP1 TMEM183A SYT9
COX19 PTGS1 PTPA PRDM5 NCAPH SNX1 UBE2D3
RPGR CCDC177 CDC25B MYO6 FSD2 GJD3 NRP2
CHIC1 KCNMA1 KLRB1 ACER3 GNA13 FBXW8 NCKAP1
AGAP3 SLC39A1 KPNA1 TPD52L1 ADNP CNTN5 MBD1
PHTF2 VWA2 PLAGL2 ARHGEF12 USP47 MTMR11 AREL1
CD209 DUOXA1 CCL4 SLMAP FAM107B BIRC3 KIAA1549L
NR4A1 KCNJ15 SDC1 NKAIN3 XRN1 AK4 RALGPS1
YOD1 ZNF468 ASTN1 MBNL2 EIF4E3 TLR6 SUSD6
DNAI4 GDNF RAB7A ARPP19 PTCD2 TMEM154 WAPL
SLC12A2 ZKSCAN8 PCYT1A DCUN1D1 LYSMD4 RNF150 ZBTB20
TBC1D16 NUP155 TROAP TGFA TPD52 FHIP1A CNNM2
ZBTB18 FBXL7 HMX2 HEMK1 EYA1 SEMA4D AP5S1
MARCHF8 FRS2 CERT1 PCDH9 KIF6 KSR1 JPH1
AMZ1 EDIL3 CCT3 ACSL4 CECR2 RBFOX2 MS4A7
ZNF75A LYPLA1 LAPTM5 B3GNT2 CTBP2 SEC14L5 MASP1
SLC2A10 ATP7A RPGRIP1L RACGAP1 CERS3 CDC42BPA CTSH
STPG4 GNA12 TPRA1 PIAS1 DHFR ZBTB5 KIF3B
THRA GAPVD1 NHEJ1 STS TMCC2 ASXL1 GFRA1
CD164L2 CDV3 EN1 ZNF436 TTC39A IRF2BP1 CD6
BCL6 POLR1B CHRNA7 OR14J1 SLC9B2 RAB23 ZBTB43
GINS1 RIMS2 LIN52 TRIM56 CD55 KLHL3 TBL1XR1
GRM5 ZNF341 ZC2HC1C SH3BGRL2 CCL28 GALNT7 SOD2
TCEAL6 GUCD1 PPP1R18 PSD2 ZNF639 GSPT2 FLRT2
EPSTI1 RBM7 PARP9 GPR174 MLEC UBE2W ZNF544
YTHDF1 TMEM132B P2RX6 FOXP1 KRBA2 TXLNG B4GALT1
EYA3 SUMO3 KLF6 RPL13 LNPK UBFD1 BRWD1
ZNF217 THSD4 CNDP1 GBP4 NAT9 EIF5A2 RNLS
SMC1A CENPW MBTD1 PALM2AKAP2 ZFP90 ABO SCN3B
GABPB2 AIG1 ZNF517 MACROD2 ARHGEF6 GALNT1 SLC6A4
KLHDC7A VEGFA SMIM10L1 IRAG1 SETD7 FMR1 RBM23
DCX ITPRID2 CEP350 ALKBH3 MRTFB RAB3B GLRX
ADAMTS17 STK32A DIDO1 GIT2 TNFAIP8L3 SLAMF1 TGFBR3
PEX26 DMPK LPCAT3 YWHAZ PLCB3 SRPK1 CCNT2
TNNI1 TTC7A SPP1 CHMP4C UVSSA STC1
FHDC1 PHLPP2 COMMD7 FAM241A BNC2 PDXK
GUCY1A1 COPG2 AMPD2 RDH12 ENTPD6 ARL3
ZNF74 POLDIP2 KLHL36 ABHD2 RPS6KA2 KIF2A
PRMT8 NBR1 MPZ GPR26 PLEKHO2 XPR1
GDAP1L1 HNRNPR CHFR SEMA6D APOL6 ONECUT2
PEX5L ZNF417 SMC6 ZNF398 ZNF442 PTBP3
RNF165 EIF4B STOML1 ANAPC16 GABARAPL1 PDK3
RIT1 WNT8A ABR MALT1 THAP2 KLC1
ZNF382 ANKRD42 PAX1 CSNK2A1 PCDHA4 RGS4
SLC20A2 RAB11FIP4 LIF PAK5 MRPS5 MANBA
FGF1 RPL10 GPD1 IL21R RBM48 TRA2A
GRIA1 USP6 ZNF451 ORC4 TMEM164 USP25
HMBS MED20 ATP5F1A BTLA ZBED3 METTL8
ZNF501 ZNF827 BOD1L2 UBE2I ZBTB37 CAMK4
MSH2 PLEKHG3 ITPRID1 MRRF RSPO3 TACC1
CLPB CCNJL EFTUD2 PEDS1-UBE2V1 ADO LOC112694756
PKD2L2 TSHZ1 EPS15L1 SERTAD3 B3GALNT1 FAM149A
SLC9A8 AAMDC RPS3 PLPP6 STX1B HECTD4
NOL10 AGO1 CALCOCO2 GAB1 EXOSC6 IRAK2
TSN CHCHD7 PTGES3L XKR5 CNTNAP5 FXN
PDPK1 CARD19 ZNF484 SART3 OTUD7A SLC11A2
CDX2 SALL4 CDS1 IFT140 MBNL3 HMGXB4
FAM13A AK2 SMC2 POU2F1 MTO1 ZXDC
ZNF211 GMEB1 UNC45B KIF5C KCNK10 WTIP
PSME3 ZNF326 PLEKHB2 NCBP2 RHBDL3 NCBP3
CREM ZDHHC23 CTCFL SIAH1 BACE2 ATXN1
TBC1D2 KIF1A ANKRD46 LRRC63 TOR1AIP2 CACNB4
MGST1 MATN4 G6PC1 PRKAG3 SKA3 TTC39B
ZNF850 DICER1 RXRB MGST2 ZNF641 RAB3GAP1
PSMD5 SPHKAP CDK2AP1 SEMA3A CCNYL1 PEG10
CDC42EP3 FCRL2 STOM SREBF1 ZNF555 MAMLD1
PSMD11 COG3 KLF7 SMAD2 ST6GALNAC3 GFOD1
CHD2 SESN2 NFIX CHEK1 PRICKLE1
PCED1A SYT15 ZNF512 GLYCTK MRPL42
CALCRL TSSK6 SEMA4F UTP25 APBB2
ITGBL1 C19orf44 PUS7L NEK6 LSM11
CEP57L1 SLITRK6 RCN2 SULT1B1 CLVS1
SZRD1 RTL6 AAGAB CCDC144A PGM2L1
SRGAP2B TCHP STK25 KIAA0408 OR7D2
KIF27 NTPCR RAB4A PHACTR2 PSMF1
SLIT3 PRXL2A KCNT1 AAK1 GPAT4
ITPRIP LCOR LRRC14 KIF1B HNF4A
PRKAR1A DCTN5 RPS6KB1 SNX13 LDLRAD4
LZTFL1 PARD6B CHD4 DENND5A CUX1
HOMER1 USP32 BBX ANAPC13 ZNF778
ZNF550 CBR4 ELF2 INTU ZNF605
WDR72 ZNF587 ZNF891 DCAF8 UBE2L6
FMN1 SEC22C POTEI CNR1 GPRIN3
ANKRD62 TRIM4 GANAB GOLGA7 CNNM3
RFPL4AL1 LMLN CLCC1 RAB9B DSTYK
SDHC FGF5 LMCD1 ERAP1 GAS7
SLC38A1 KRAS PTPN5 RGS3 QKI
ACVR2A TPGS1 CARHSP1 CDC37L1 NFASC
MYBL2 LUZP1 LILRA1 EPB41L4B RNF213
RANGAP1 PLEKHG4B ACTN2 SLC35E3 RPRD1B
FBXL4 FCRL3 PHYKPL NUP107 LRRC3B
REXO4 DNAJB6 RHOH SPC25 RUBCN
JRK KCNG3 COBLL1 TAOK1 NPY4R2
DPF3 RUNDC3B MDM2 HOXD11 ADCYAP1R1
ZNHIT3 AKAP7 MON2 SRPRB SEC22A
MAP2K4 MSI2 GPATCH11 PELI2 FBXO3
SMAP1 CD151 CRNKL1 PROK2 CLUH
UPK1A MRPL30 SSTR3 XPNPEP3 ZNF701
SLC35C2 APOBEC3F ELN TMEM38A CBFA2T2
MCM8 TNFRSF10B PHB TTC13 EIF2AK2
RFX3 SVIP HEPH GALNT12 REEP1
SSH2 HGSNAT PYCR1 RBFA MMS22L
PPP2R5E AMER1 OSCAR CCDC134 EML1
WFDC1 TLCD4 ARPIN DLST ALDH1L2
ZFP37 PGBD4 MDH2 HSPA4 MTERF4
FAM243A METTL15 KCTD14 KPNA4 TRAK1
H6PD NATD1 GOLGA8M NDUFB5 PTCHD4
ARSL IP6K1 GOLGA8H RAD51D TTBK1
FAM107A BEST4 GOLGA8K SRP19 NCOA2
HEY1 HYAL1 ZNF343 VSNL1 ZNF276
TRIB1 ZNF791 BTBD3 ACOX3 NHSL2
CIBAR1 LNX2 HHLA2 MPDZ MKLN1
ZFYVE16 ZDHHC14 ZCCHC17 GPRC5A CELF2
VOPP1 KMT2C SLC66A3 PRDX6 MAPRE2
FKBP9 RASSF2 KIAA1217 PPARA BMP10
LRRC49 TEDDM1 CCNY CCDC6 FAM131B
SLC36A4 RDH10 RASGEF1A KARS1 PTDSS1
SLC2A14 DCUN1D3 MTSS1 NFIB MRPL19
RALGPS2 CNKSR3 AP1S1 ABI2 ARNT2
PKNOX1 DNAJC5G USP8 EIF1 ZNF652
MRS2 ARL10 EIF3J LANCL1 ZNF507
TUBGCP3 JAZF1 LRRC28 CAPZA2 ZHX3
PPIL6 SPDYE1 UTP15 POLD3 SAMHD1
TMEM179 GATC FAM234A DBF4 OPA1
RNF217 TUB OPRM1 FAF1 FAM169A
CIITA TMEM26 FAM168A PXMP4 YPEL5
RNGTT CMTM4 TAF1 BRCA1 DNAJC27
KIAA0513 SRPK2 DTX3 PGLS SHC3
RNPS1 SP8 VTA1 NUPR1 ADD2
SYNPO2 MACC1 TRIM40 EPN1 TMEM127
NTMT1 ATF4 MON1B TRHDE PRR11
FARP1 PXDC1 MLLT3 PNISR RSBN1
FSD1L CREB3L2 ACSL1 CX3CR1 STRBP
XKR9 NAIF1 BORA SMIM10L2B PAG1
IQCE RINL CRISPLD1 SPDYE11 ERMAP
CLTC APOOL PCMTD1 SPDYE17 KLHL7
ELP4 LONRF2 CBR1 C4orf54 WDR5B
DNM1 CIBAR2 CNOT6L ATP2B1 ADCY2
ABCA8 NHLRC1 DCAF10 PTAR1 PDP2
PLAGL1 SIAH3 PTTG1IP SPDYE14 ZBTB4
FAM104A TPD52L2 HECW1 SPDYE8 EPB41L5
PRMT7 MOB4 KIF17 SPDYE15 ADCY1
CEACAM7 GPX1 JADE1 SPDYE9 INIP
IGF1R CLEC12B COL4A6 SPDYE13 XYLT1
WASF3 GADL1 CYFIP1 MCTP2 LMBR1
CDC27 NEBL SNTG1 IMPG1 HHIP
CCR1 YKT6 TMEM9 CASR HAPLN4
MIER3 ETV1 CST3 CD44 KLHL18
CCDC125 ARFGEF2 CSF1R REEP3 VCPIP1
C1orf43 ANO6 DBNDD1 OR4N5 HAPLN1
MAMSTR PAFAH2 TMEM273 OR6B1 AFF2
ZNF546 PPP6R3 VSTM1 BIRC5 FNTA
TSEN15 KLHDC2 RMND5B SOGA3 KLRD1
LYPLAL1 LOC102723728 ZNF585A KATNAL1 PRKAR2B
SYT7 TXN2 LAIR1 MECR PRPS1
CDK19 GPR55 DLD CSKMT QSOX1
EYA4 KCNK9 ZNF761 TF KCNK5
TRPM7 KIAA1958 UHRF1 ATG9A BMPR1A
HMGB3 PGAP2 SEMA3B RAP1GAP2 SPTLC2
DEFB134 NWD1 TIMM23B PAK3 IDE
TMEM198 COL20A1 MYADM SLC2A5 SMAD4
HAUS3 SLC30A3 CDIN1 CCDC85C INHBC
PRKACA ITPR1 SLC35E2B PTPRQ LPP
ZBTB26 SAV1 ZNF304 ANKRD34C DCAF7
CEP20 WNT10B CYB561D2 ANKRD33B PITPNA
PRKAG2 TUT4 SH2B3 TK2 UQCRB
GPX8 POTEB3 ZBTB8A CXADR SEC24B
SERPINB13 MTMR9 REL RAB35
MAP4K2 TTC34 KLRF1 SLC2A3
ELMOD1 SNX27 MTR ZNF81
TNS1 CEBPZOS CDH18 PHLDA1
SENP5 PLEKHM3 RUFY3 PITPNB
NEURL1B ING5 SGK1 WBP2
CPEB4 TMCC1 CLNS1A DSE
GCLM TPRG1 MYCN MCTS1
PGPEP1 SH3RF2 CA12 DBNL
SLC38A7 HEY2 SEPTIN9 HDAC9
THY1 HNF4G LYRM7 CTSO
BLOC1S6 HPSE2 ZNF131 ARL17B
RHOA SCAPER HSPBP1 KCNJ5
LOX PLEKHJ1 CNGA3 PPT1
ZNF331 PRIMA1 CIRBP VMA21
TRAM1 ATP2B3 FRMD8 SLFN12L
PPM1L SLC4A4 ZNF562 LRCH3
ZKSCAN5 SLC6A11 KMT5B OTUD4
LZTS2 SLC25A15 EMSY ZNF577
NINL TENM1 DLG2 MAPKAPK5
CCDC157 NPTXR NUDT4 ADPRHL1
ZFP1 SMUG1 CADM1 NBEAL1
TRAPPC4 CRCP NDST1 ZNF142
STK32C GOLIM4 ZBTB44 SPECC1
OPCML HERPUD1 ERC1 RNASE10
RILPL1 EEF1AKMT4-ECE2 TMEM98 SFMBT2
CAMKV DAZAP2 UMAD1 OR10A6
NRXN1 TSC22D2 AAMP BMP7
U2SURP TRIL ACHE SLC26A4
FAS TECPR2 CEP97 GABRA1
BNIP2 PPM1E SMIM21 GUCY1A2
LPGAT1 RRP1B VBP1 HTR4
MCF2L WDR43 CD226 OPRD1
WDR82 OTUD3 OLFM2 PTGIS
TTYH3 KIF13B LMOD3 IL17REL
NDFIP1 VPS39 HMG20A OR8D1
LRRC27 ANGEL1 KRCC1 SPIN3
DDHD1 AHCYL2 CYREN FAM102B
CYRIA TMEM158 ZNF236 SNX30
TXNDC5 UBXN7 QDPR SERF2
APOLD1 GPX7 DAPP1 YTHDC1
OR2J2 MED15 CCT5 HIGD1A
ANP32E PHF20L1 TGFBR1 VSIG4
AMMECR1L RTRAF TCF12 AUTS2
TRAPPC9 IRAK4 ZYG11A AP4S1
MARVELD1 A4GNT UPRT ARHGEF3
CACNG8 NCKIPSD DYNAP CALU
CCNB1 PAX5 ST8SIA5 KCTD1
PCDHGA6 TRIT1 LIPG NEMP2
CAPRIN2 TENT5C PIK3C3 SIN3A
PLXNA1 THUMPD1 PHC3 PDCD6IP
EIF1AD HIF1AN ZNF24 STX3
LLPH SLC30A6 SYT17 SRSF10
DDI2 POLR3B SS18 TMEM178B
COG8 EFHC1 SSR3 RUNX1T1
MSANTD4 GOLPH3L ZNF346 SLC28A3
JAGN1 PARVA NME6 TMEM235
KRTAP4-4 SLC47A1 NAA50 TAF1C
TRIM63 UQCC1 MGME1
PAPOLA CMTR2 AURKB
MAFG MINDY1 MYMX
SFT2D3 CHST11 CCDC141
ZC3H10 GABRQ SPC24
SYAP1 DISC1 BLCAP
SPPL2A WDR4 CTSB
ITIH5 ERBIN ARIH2
SPRYD3 FBXO42 CDKN2AIP
PRPF38A ANKIB1 THAP6
TMEM241 WDR44 BCL2L1
KRTAP4-11 VSIG10 AQP7
SYNE1 CHST7 SLC35E4
ZCCHC3 HMCES ZNF532
SLC45A3 STOX2 BICRAL
PML CDC42SE1 FHL2
SMDT1 CLDN2 LSAMP
CDC14B JPH2 FAM216B
CFAP91 AICDA PRCP
MVB12B SERINC1 NUMB
DISP2 TBC1D14 BCAS3
TPD52L3 ZBTB2 DMAC2
FGF13 TRPM3 MED28
CDH7 BMP5 KDM7A
CORO2A MTMR3 ATXN3
WDR7 CLDN1 OR2H1
AZIN2 DMTF1 C1QTNF3
ZFP91 PSAT1 PHACTR1
MYLK ADAM22 ADAMTS12
TEKT1 FOXA2 SFXN3
BSND OPTN SLC25A28
FBXO32 PRSS22 CDK13
SLC36A1 IPPK DNAL1
COL9A1 DDX50 CRISPLD2
PTPN2 IRF2BPL GRWD1
C20orf96 RPAP2 CACNG6
CST9L PRR5L ESYT3
SRXN1 CNR2 KLF16
WFDC10A COL4A1 PCBP2
ASB16 CTSG TMEM245
COLEC12 FCN1 ZIC4
DPP8 HOXD10 ZNRF3
UBE3B LY75 ZNRF1
INPP5K MN1 LRRC8C
ZFP82 NMBR HSDL2
HPCAL1 OMG CCDC77
PANK1 PFDN5 ARFGAP2
GLB1L2 PIM1 MEGF11
ZNF251 PREP SPIRE2
MARCHF9 MAPK13 CNFN
CMTM7 PSMB2 KBTBD8
ARL11 SCN9A BOK
DDX31 ITSN1 NT5C1A
BCL2L11 SH3GL2 ST6GAL2
NFAT5 SLC7A2 ZNF594
SPATA17 SPARC SLITRK2
VANGL1 MAP3K7 USP38
NRXN3 VCL MFSD14B
SPPL3 ZNF84 INA
MAPK9 HMGA2 TXNDC17
SREK1 TAF15 ZNF496
DNAAF8 RANBP3 ADGRA2
TSTD2 DGKE ZNF514
PPTC7 DENR CEP89
CLDN14 ASAP2 PDGFB
TBC1D2B ARHGEF7 TSLP
MAPK1IP1L MBD2 GTPBP10
ATP6V1C2 EFNB2 NKD1
ZFYVE27 COL12A1 CNP
C15orf40 DMP1 GABRG3
NIPA1 FOXE1 ADAM19
CMTM3 ILF3 TNKS1BP1
UROC1 RAD9A DMAC1
FAM76B RAB11A LARP1
GLT1D1 VAPB GADD45GIP1
SEPTIN10 MAGI1 RFT1
KLHL23 IER2 SLC2A13
EFHB DHX8 ELFN2
SPICE1 SERPINI1 WDFY2
FAM91A1 CD80 NIBAN1
FAM124A CDX4 ARTN
UBQLNL SKIL KLHDC3
C18orf25 ARHGAP6 NAA15
PIGM NCOR2 TRIM6
DIRAS1 SPTLC1 BORCS5
AFG1L ELL BRD4
PDCD4 RRAGA BANP
WFDC5 TCFL5 B3GALT6
APOBEC3A LMO4 TMEM41A
TIGD1 HNMT SLC46A1
CACNG5 SRP72 DYNLL2
HS6ST2 WASF2 SIRPA
FOXP2 ZHX1 SOCS4
OSBPL9 DUSP12 MUCL3
RPUSD2 KLF12 DBN1
C1orf158 DNPEP WRNIP1
C1orf216 GTF3C4 TSPAN18
JMY MRAS SYCE1
APOBEC3D KPNA6 SNAP25
CEP128 SEC61A1 WIPF2
ZNF362 SNX12 GSX2
SNRNP48 NRBP1 PLCD3
TBCEL OSTM1 CCBE1
ELAPOR2 TRPS1 BMPER
SCUBE3 HNRNPH3 MED22
TMEM18 UROS RORA
TMEM268 PISD ZNF845
TNPO1 NEK9 DHRS1
MFSD4B METTL21A FOXP4
ODF2 CCDC40 TLR4
LTO1 CEP78 MPLKIP
HS6ST3 ZNF383 CANT1
CREBRF FBLIM1 ANKRD54
CALHM5 MGAT4C A1CF
C10orf67 ZNF843 MS4A6E
MEIS2 GCK KCNH5
SKP1 NT5C3A YWHAB
CAMK2B DCHS2 ODAD1
CAMK2G LOC102723996 NACC2
ELF1 DEPDC4 ZNF558
RELN C9orf85 CCDC13
IFNLR1 MIOS KLK11
ABCA12 LOC102724488 ZFC3H1
NFATC3 TFDP2 VSTM4
SLC38A11 GIGYF1 ANKRD23
REM2 SH3D19 ZNF25
CCDC171 NFILZ GLYATL2
RNF152 RNFT2 NSMCE1
SLC9A9 SPDYE21 SENP8
ZNF619 LCA5L OSBPL3
SLC30A8 OR6C4 DBF4B
SPATA19 TTC28 TRAF6
CNTN1 ESR2 CRYZL1
KRT73 ING2 SNX15
MT1E NCF1 IPMK
EXOC8 TPP1 TCEAL7
C5orf51 NEU1 ORAI3
PIGN PCSK1 TADA2B
PDLIM2 SLC10A2 RAB42
PATJ CYP3A7 TRMT61A
STX12 GRIN2B PIK3AP1
LYNX1 IGF2R AGBL1
RETREG3 TSR3 CDYL2
RASSF3 NOMO3 PRXL2B
SPTBN1 OR2T33 TBX15
LCE1E OR5A1 TMEM237
SPINT4 OR56A4 UGT3A1
SLC25A42 OR56B1 C5orf24
TRIML1 OR4N4 ZNF664
FBXO27 IGSF3 UBE2U
SCYL3 GP2 CNIH3
DCAF4 CISD2 ARL6IP6
NCOA3 PLPPR5 PPM1K
GJA5 DNTT MOSPD2
NF2 DAPL1 SDE2
ZSCAN22 CORO1B BBS12
APAF1 ZNF181 SGMS2
ENOX2 AP1G1 CDC20B
GATD1 CYB5RL DCP2
TMEM255B MAF SNX31
ANKDD1A NGRN DAND5
TPRG1L ELMO1 NANP
VSX2 DEDD AMER2
ERG MINDY2 MTURN
IRF2BP2 SLC6A3 COL22A1
DTNBP1 JADE3 MAGI3
TMEM107 G6PC2 PXT1
CYP26C1 POLR2J3 ZFP3
HNRNPA3 MID1IP1 SLC35G1
ZBTB41 GXYLT1 ERI1
RNF41 PACS2 APCDD1L
RNF138 KIF13A ZCCHC24
TREML4 SYNPO B4GALNT2
G3BP1 IGF1 MED19
ZNF621 PABPC4L NUP50
FAM83H PLAAT3 LCORL
NHLRC2 ROBO2 CACUL1
CCDC172 INSYN2B ZFPM1
DRAXIN MEF2A ADGRF1
LHFPL4 AGFG1 RASGRP4
TDRD1 PIK3IP1 ATP2A2
BCAS4 RPS24 RASAL2
ACACA ZNF880 NMNAT2
LCN6 SPDYE6 CAMK2A
DZIP1 CCDC81 TRIM39
ISM2 PLEKHD1 RC3H1
ILDR2 COG5 CSF1
KCNRG ZSCAN12 MMAA
CACNB2 C10orf105 KCNH1
ZMYM3 SPDYE2B LIN9
ENOSF1 NEU4 USH1G
SMIM10L2A UBAP1 PTCHD1
SYNJ1 ASTN2 TTBK2
GRB2 FBXL20 PLBD2
UGT1A6 CENPO KLHDC8B
ECI2 KATNA1 TYSND1
PRAME ATG13 ANKRD52
ENSA EHF ZNF776
FREM2 BACE1 RIMKLA
LRRC75A GHR PDZD8
BEND4 PARN RABL3
TMPRSS11F GFOD2 SLC41A1
TEX19 CDC5L PSMD12
ADAMTSL3 NKX3-1 CCDC50
ZC3H14 SEC14L3
EEF1AKMT2 ZPLD1
ANO5 DDX51
TMED8 APTX
WNK1 XG
ANKRD44 PTPMT1
KDM2B ZNF792
PEAK1 PRR18
PCGF2 FGF14
RECQL5 PSMD13
RAE1 FAM171B
METTL6 PKHD1L1
UBE2E1 ASB6
SACS SOX5
SNX9 GPR119
SYNJ2 CCDC190
ARHGAP5 ZDHHC21
DRAM1 IQUB
MICU1 HPS5
ADAR PIK3R1
SUSD4 UBXN2A
FOSL2 OPN5
CHIC2 CERS2
TRIM2 C20orf203
DELE1 SKA2
MYLK4 CTDSP1
EMP2 GPX6
ACTN4 GDF7
RPS6KA3 DLGAP4
DLG3 ADCY5
PHKA1 RNF14
AGPS FBXO25
LOC401040 SRRM4
TTC23L KRIT1
MKRN1 COPS8
STX17 CD96
NIPSNAP3B MLX
PLA2G15 HIPK1
TMEM131L SRC
NR3C2 EMB
ARHGAP25 C19orf54
GALNT16 RUFY4
RIMBP2 LRIT3
DMBT1 LANCL3
INPP5F STIMATE
ZC3H12C GJB7
HMGCR VWC2
KAZN SULF2
CACYBP KRTAP10-4
NFIA KRTAP10-5
TMEM234 MKNK2
EFCAB2 HOMER2
ABCC5 POLQ
SNCA CDC25A
SUPT3H MAFA
EXOSC2 STAMBP
RAPGEF3 SF1
TARBP2 IYD
GRTP1 MBLAC2
NTRK3 IER5L
TVP23A OR2V2
TTLL6 NAALADL2
SOCS7 PAOX
NPEPPS FAM199X
GOSR2 NIPAL1
ZC3H4 SPRYD4
ARHGEF9 MAP6
SHROOM4 PATE2
AGK SIGLEC15
MLLT10 SLC25A24
ENAH PRRC2C
EIF5A NYAP2
TCEA2 USP37
HECW2 CDK15
RBM5 HSPBAP1
LIMD1 PI4K2B
B3GNT3 ABI1
UQCRQ SLC1A2
MOCS3 IDH3A
MCAT GLP2R
OR1A1 NKIRAS2
STRN3 RARA
DNTTIP2 FOSB
FAM120A ZNF324B
NOS1AP PDCD5
TCAF1 GMEB2
KIAA0586 CRELD2
TOMM20 CHCHD5
LCMT2 PDS5B
TOX4 SLC66A2
RHOBTB1 ACAD8
SRGAP3 FAM172A
HELZ KIAA0319L
NLGN4Y MEF2D
NAV3 STAT1
CNKSR2 TTC21B
FASTKD2 SNCB
STK38L MAFK
TNIK CACNA1C
GGA2 LRP6
SPART SETD1B
TTLL12 LITAF
SEPTIN8 CCNP
RCOR1 PGLYRP4
CYLD ADAM23
CUX2 GABBR1
HAUS5 GRB10
RRP8 CEP152
BRI3 HACD3
CCDC28A MPHOSPH6
C2CD2 PAFAH1B1
CRELD1 POU2F2
DNM3 THOP1
LSM14A TNNC2
FAM184B PPM1F
WWC3 BIRC6
RRP7A ACTR8
COL5A3 PDE10A
KRT76 ATG14
ST8SIA3 POMT2
ZMYND10 SRGAP1
RWDD1 CEP290
GAL ZDHHC6
ABHD5 SPOCK2
DHRS7 ZMYM1
RLIM GNG4
RAB10 BIN3
MRTO4 PPIH
HECA CHRM3
DCTN4 PODN
CYB5R4 NPHP4
NLK TLR5
AKAP11 CYP27A1
CAB39 EAF2
WBP11 TGFBR2
GULP1 BAP1
RAPGEFL1 ADGRL3
ZDHHC2 LARP1B
PHF20 OGFRL1
BET1L AGFG2
UFM1 FGFR1
CYRIB TUSC3
C21orf91 ANKS6
EPHB2 SNAPC3
BAIAP2 ASAH2
NPTN CPT1A
PLXNA3 RBMS2
LEPROT DCAF5
PARP14 PNPO
TRIM44 SMIM5
DIRAS2 PIGL
KIF21B ABHD12
ZNF280D TAB3
GDAP2 GALNT11
LRRFIP2 ASPH
UHRF1BP1 CC2D2B
CASZ1 RPS6KA1
NSD3 CNTN2
DEPDC1 TNRC6C
SARS2 TXNL1
PIGX IL18R1
GID8 TIGIT
TTC38 UBL4A
VPS37C CLEC4M
TMEM248 ADAM28
IFT57 CAPN6
CCDC186 TNFAIP8
PRPF38B SND1
ANO10 TMOD2
ARMC1 TMEM97
KLHL11 SOX8
N4BP2 HERC3
SBNO1 KIAA0040
ARL8B PHF14
MACO1 EDEM1
MOB1A AQR
RCOR3 SECISBP2L
TMEM19 ZNF536
C5orf22 RNF144A
AGPAT5 SERTAD2
LIN7C EPM2AIP1
SYNJ2BP PLPPR4
BEX1 KBTBD11
GPALPP1 ADNP2
CHST12 CILK1
RBBP6 ADGRL1
CTTNBP2NL ZNF365
SLC30A10 RPH3A
OTULINL SV2C
SPATA6 TNRC6B
UGT1A10 RAD54L2
UGT1A8 PHF3
UGT1A7 LARP4B
UGT1A5 TRIM9
FGF20 FBXO28
TCIM MINAR1
SAR1A POFUT2
RAD18 MGRN1
CMC2 ADCY6
NIT2 SASH1
OTUD7B DPY19L1
DTWD1 ESYT1
CDC42SE2 PHF24
TULP4 SRGAP2
ARRB1 ZNF10
MNT SPEF1
SLC39A10 CAMSAP1
ENTPD7 ATL3
XPNPEP1 NOL11
PLXDC1 RAB11FIP5
ADCK1 DKK3
LYRM1 NUDT13
SELENON TRIM33
NHSL1 TPPP3
NDRG4 UBE2D4
RHOJ KLF13
HEG1 FIS1
AARS2 HDGFL3
MIB1 INSIG2
TRMT5 SUFU
CCDC191 IKZF2
ZFP28 AK3
MEAK7 PCYOX1
SLC7A14 ACP6
LZTS1 ANKFY1
UGT1A9 SCLY
TMSB4X KLF3
RNASEL ERGIC2
NEUROD4 SLC25A37
NTN4 ZNF771
RBM25 FZD3
BCR SIX4
PBOV1 SPA17
ADAM12 CPSF2
FAM3A NAGK
TWNK OTUD5
MCL1 SAMD9
ZNF148 GIPC2
LAMTOR3 FERMT1
KCNK13 NUP62CL
KCNK12 BIVM
NAPB CWC25
CLSPN RPP25
TSPYL2 NHP2
CLSTN2 PHIP
RAB38 ZNHIT6
PDF ARGLU1
NCAPG ATG2B
ABCG8 MANSC1
NSD1 NODAL
GREM2 RIC8B
ATPAF1 CCDC198
CERK CKAP2
NIBAN2 UBA6
BCL11B BRF2
C8orf33 SPTLC3
FUNDC2 SLC39A9
C1orf116 FOXJ2
TMPRSS3 TMEM242
PRRG3 ASAP1
MBOAT7 ZC4H2
TMEM43 CEP41
DSC3 AJAP1
ADIPOR2 PCDHB14
GALNT14 PCDHB15
EFCAB1 PDE7B
TUT7 ERRFI1
RTL10 HOXC5
VPS37B SSH1
SNIP1 CCSER2
IQCA1 TMX3
MOB3B ING3
ATP8B4 SEPTIN3
ACTR5 PPP1R37
FBXO17 HOXD8
POF1B LRRC8A
DOCK5 C21orf62
GFM1 SERTAD4
ASRGL1 ACRV1
NYNRIN FEM1C
CENPA C5orf15
CKS1B INCENP
SLC31A1 COQ8A
DR1 ZMIZ1
DRP2 SLC24A2
DSG2 PCNP
FGF4 LYZL6
FRK THAP11
GABRR2 RTN4
GFPT1 RCN3
GLUL KIAA1143
GNAQ GATAD2B
GTF2E2 LRRC47
GTF2F1 USP31
KDR NLN
LAMA4 CCPG1
LAMC1 NLGN4X
LIFR MTUS1
NDUFA4 COG6
NEO1 PCDH19
NPTX1 RTL9
OR1D2 NUFIP2
OR3A1 IFT80
PPP2R1B RELCH
PRPSAP1 SHROOM3
PSMD7 CALCOCO1
PTPN3 PLXNA4
RAP2B GNAO1
RBL1 ZNF253
RGS12 ZNF250
RYK ART4
SBF1 CCAR2
SH3BP2 LY6G5B
ST8SIA1 IL21
SOX11 FGA
SSR2 ITM2B
SYN2 TIA1
TAC1 NXF3
NFE2L1 MRPL17
TEF VIPAS39
TRPC1 STEEP1
UBE2G1 EPB41L4A
UBE2N ERAP2
VLDLR NXN
WEE1 SUDS3
WNT2 VPS52
ZNF177 GPR135
SNN PRRX1
ULK1 SLC13A3
VAPA MRPS11
GCM1 INTS3
TRADD ZBTB10
CDS2 ZNF426
CCN4 DSC2
MBD4 PSTPIP2
KYNU WNT2B
USP13 FYCO1
INPP4A NKAP
EIF4EBP2 RIC3
AKAP6 MPZL1
ATF6B MAP7D3
ELF3 NAA35
ETV5 YRDC
FGF10 LRRK1
VEGFD ASB13
FOXA3 TXNDC15
MYT1 SNX22
PEX14 L2HGDH
GET1 SCD5
COIL NAA25
LIN7A IFT74
DCLK1 CLU
PIWIL1 GOT1
B4GALT5 HOXB5
UBE4A IDO1
KCNK6 IFNA8
SH3BP5 LRPAP1
PCYT1B LSS
AKAP5 SH2D1A
SEC22B MARCKS
MYO1E MCC
NDUFA9 MSR1
NFKBIL1 NFX1
SNU13 NOVA2
OXA1L OAS1
SCD PAPPA
ZMYM4 PBX2
ADAMTS4 PDCD2
THRAP3 PDGFRB
CLEC2B PDK2
FOXL1 PLN
GPR15 POLA2
HAS2 PPP2CA
PRKAB2 PPP6C
CCL13 PRKACG
AKT3 PRKCB
MLANA PSMA4
HOXA11 PTMA
IFNGR2 PTPN4
LAMC2 PTPRG
SOX3 RAC2
VAMP7 CCL22
FARSB XCL1
ABCC4 SDC4
SAP18 SFRP4
GOLGA3 SHB
MAP1B SLC6A1
CD164 SLC18A2
ALKBH1 SSR1
HTR3B SUPT4H1
HS3ST3B1 TFAP2B
CITED2 TRAPPC10
NTS TNNC1
ORC2 TRHR
PAX9 TXK
ENPP1 UBE2B
PHKG1 UBE2V2
PRKAA2 WNT5A
NCOR1 ZIC1
RBM14 ZNF141
TRIM38 BSN
EIF3M BFSP2
ARL6IP5 CUL4A
MTHFS TPST2
PAICS SMARCA5
P3H4 GPR65
POLR3F PARG
GNAI3 NIPSNAP1
HIC1 TP63
PVR AOC3
HBS1L CHRD
MTHFD2 IRS2
MMP24 KAT2B
NUDT3 ST13
SUGT1 RNF8
DNAJB2 FKBP5
AP3M2 GMFB
CKAP4 SLC1A1
TMED10 SNRPD3
RAB31 USP2
ZFHX3 CHST2
IDH3B GDA
RASGRF2 ARHGDIA
DDX52 ELAVL2
ADAMTS5 ETFDH
NISCH FOXD2
CEP250 HNRNPC
SEC23IP SCO1
RNF139 PIAS2
KLHL2 RABEP1
MME ATG12
BRD3 RPS6KA5
ATP1B4 ASIC3
ELL2 B4GALT6
CHRM5 BAG5
CLDN12 APBA3
TIMM10B CDH6
KCND2 DOCK3
LDOC1 GABRE
MYCBP KCNC3
PRND KCND3
POLM NUCB2
CDIP1 ABCD4
OR10H1 TLE1
PAX8 AKAP17A
CNTNAP2 EXOG
PRKAR2A ABL1
PMS2 ATP5MC2
NUTF2 CBL
CDKL5 CBX2
ZNF197 FOXN3
ZEB1 CRK
CSTF1 CRKL
HMBOX1 ERBB4
LRP10 HSPA1A
PLEKHA7 CNOT9
SRGAP2C ZRANB2
ASB1 KCNE3
MOK CFL1
TIMELESS ITK
POLA1 KRT6B
CYB561 TAF11
POU6F1 VDAC3
AKT2 RNF103
LRRC7 TSPAN5
CMC1 CNIH1
TMEM72 SPRY3
CEP83 MLLT6
DLGAP2 MMP16
DYRK1A MTF1
AR HDAC4
ZNF525 PRICKLE3
TBC1D5 NRGN
HSPB7 PRKG1
ICA1 DNAJC3
SLC8A1 HOXB13
C13orf42 VTI1B
DAZAP1 CRTAP
CTXND1 AGPAT1
PSME3IP1 TGOLN2
BRAF ERF
BRD3OS PSMC4
EPM2A TRIM27
DIO3 DYNLT3
TCAF2 EXOC5
PDE1A DCTN6
NR3C1 FUT9
MGAT1 KIF1C
FAM243B HPSE
TENT4B SPIN1
KLHL33 ABLIM1
DAB1 FKTN
GPRC5C SCML1
KPNA5 KRT38
CACNA2D1 ZBTB33
FAT3 ATF7
ALDH5A1 ZFP36L2
FGFRL1 CALM1
AKAP12 ATE1
POLR3G KAT7
CTXN2 ZXDA
CRYBG1 ERG28
FBXO41 RNF2
TMEM217 PMF1
DNASE1L2 ABL2
STXBP1 PSEN1
PNPLA1 AP4E1
LOC100133315 DGAT1
PDE8B ADAT1
XIAP AP3M1
IRS4 ARL5A
HNRNPCL3 DDAH1
PRRC2B CCNDBP1
TDRP DNAI1
AGTR2 FBXL3
DTNA FBXW2
USP54 FBXO7
ELAVL1 TRIM32
GATM MLYCD
HSBP1 OGA
ID4 SLC35A3
IFRD1 MORF4L2
CEACAM1 TRAM2
BTG1 OR2A5
COL4A4 PITPNC1
ERCC6 TINF2
SHH YWHAG
ITGB3 DNAJC15
JAK3 VPS4A
KCNA1 RBM15B
PRNP EEF2K
SOX9 BLNK
TGFBI SNX8
THBD PCDHB1
TPM1 GREM1
BLMH RAX
IL2RA NRG1
UGT1A1 LIG3
EPX CRIPT
CRX TOM1L1
BCL2 FAM156B
CHRNB2 CD99
GRM6 ASAH2B
HTR1B NDUFA10
IL2RB ADAL
KCNJ2 PYCR3
OPRL1 CALM3
PRRG1 CTF1
RPL11 NDEL1
RPL28 DRG2
OR2A14 SCYL2
PIM3 GLDN
ASTL SAP130
ERICH3 SMYD1
STUM L3MBTL4
DUSP29 USB1
BMF TOP2B
NRARP KLHL26
OR5M3 ZNF287
GBA OR2J1
ZNF780B CHD1L
PLA2R1 ZDHHC24
LMBRD2 KIDINS220
NEXMIF GRAMD2B
USP20 DGKB
DNAAF9 NT5C2
C1QL3 TIAM1
GOLGA7B PCDH15
SLC9A4 TMEM269
CREB5 ZNF214
OLA1 CXCL8
KRTAP5-10 NUDT4B
PABPC1L2A GOLGA8T
PLIN5 CCDC163
DGKK RNF227
CARS1 FRRS1
LGR6 NAGA
BCL7A CYP4A11
YIPF5 RAB41
CD34 NOTCH2NLB
SLC35F1 NOTCH2NLC
RGS7BP BAALC
MTUS2 DLG1
ZNF704 RGMB
ARL4A TTC8
FOXK1 BCLAF3
TRIM71 MAGT1
TESMIN ZNF479
TYW5 ZBTB3
RSPO4 ORMDL1
TMEM70 GABRB2
LINS1 HP1BP3
PABPC1L2B IKZF5
INSC GLI2
EIF4G2 LRIG1
TTC14 CNGA1
ZNF391 BDKRB2
UBXN2B CHML
FAM110C ATXN7L3
LDB3 DMAC2L
CCDC88C FUT1
MYBL1 GPRIN2
EPHA6 OR7E24
CACTIN KIAA1671
TMEM120B DPYSL3
ZNF112 FXYD3
ARSA IRGQ
ZNF207 OR56A1
RNF169 HTT
TIFAB ERN1
SH3RF3 GPC4
ZNF578 GDI1
PIP4P1 GSTA4
CNPY1 MR1
RPP30 ACTA2
PCMTD2 AHR
SRRM3 ARCN1
PRH2 ARSD
TENT2 ATP2B4
CFLAR ATP6V1C1
EIF4E POLR3D
ZNF720 CCND2
AKR1C2 CD38
PAX7 ENTPD1
SMIM13 BCHE
ANXA2 CD40LG
ATXN7L3B ERCC8
VASH2 SLC26A2
C1orf198 GNAT1
CISD3 LIPA
FAM13C MYL3
CROT NDP
ZNF534 PDHA1
NSMAF PGK1
CCDC169 SERPINA1
RFPL4A PKP1
CASTOR2 SLC5A1
PPP1R3G HOXA13
INTS9 NOS1
UBE2QL1 ADH6
NONO ALDH2
SCRN1 ATP4B
MTFR1 CHRNB1
NCEH1 CYP1A2
RBMXL1 CYP11A1
STAU2 GLRB
TLCD2 GRIN2A
ATP5MGL PTGFR
ZNF268 NCCRP1
TNFAIP8L1 ZNF429
TRMT2B SPOPL
AMMECR1 ARHGEF37
ZNF559-ZNF177 CLDN18
CPEB2 RABL2B
VIT DYRK3
SEMA3E GRK6
SLITRK4 ZNF774
NIT1 KRTAP5-2
GIMD1 OR1B1
ATP6V1FNB OR10H5
EFCAB13 OR2L3
CCDC179 OR4K17
ARPC4-TTLL3 OR52E4
PHOSPHO2-KLHL23 LRRC55
ST20-MTHFS OR10G3
BMP2 PLCXD3
BMP3 SLC25A25
CTSV WDR35
ANKRD12 COA5
ELOC C1QL4
SLC19A1 MXRA7
MFAP3 SHE
CD99L2 TTC7B
ZNF322 ZC3H12B
ELOVL5 MYPOP
RANBP6 NUDT17
ZNF124 OR2G6
TRA2B C2orf68
TRDN GDPGP1
Details are in the caption following the image

3.3. Enrichment Analysis of Differentially Expressed Genes

To explore the potential biological functions of the above downregulated-expressed 25 mRNAs, we performed GO annotation and KEGG pathway enrichment analysis. The enriched GO annotation included oxidoreduction coenzyme metabolic process, pyridine-containing compound metabolic process, and nicotinamide nucleotide metabolic process in the biological process (BP) category. Sin3 complex, oligosaccharyltransferase complex, and tetraspanin-enriched microdomain were included in the cellular component (CC) category. NAD+ kinase activity, oxidoreductase activity, and beta-1,3-galactosyltransferase activity were included in the molecular function (MF) category (Figure 4(a)). KEGG pathway analysis showed these genes were mainly involved in various types of N-glycan biosynthesis, nicotinate and nicotinamide metabolism, and pentose phosphate pathway (Figure 4(b)).

Details are in the caption following the image
Details are in the caption following the image

3.4. PPI Network Construction and Validation of Predictive Feature Biomarkers

We further analyzed the protein-protein interaction (PPI) network of the above 25 intersected genes by Genemania and identified the RB binding protein 4 (RBBP4) had the most interactions in the network (Figure 5(a)). Furthermore, we performed the LASSO algorithm to narrow down the above 25 intersected genes and identified eight key genes related to IS (Figure 5(b)). The eight genes were BCL11A, RNLS, UBFD1, STT3A, NADK2, GPR26, PPARA, and SAMHD1. Moreover, we used ROC curve to estimate the predictive value of the eight genes, and found that all of the eight genes had a certain diagnostic value in discriminating IS patients from the healthy controls, with an AUC of 0.7 (Figure 5(C)).

Details are in the caption following the image
Details are in the caption following the image
Details are in the caption following the image

3.5. Immune Cell Patterns in the Peripheral Bloods of IS

Given that peripheral immune system has been shown to play crucial roles in the evolution of ischemic brain damage [27, 28], we further compared the different immune cell patterns of the peripheral bloods between IS patients and normal controls from GSE22255. As shown in Figures 6(a) and 6(b), M0 macrophages and resting mast cells were significantly decreased in the peripheral bloods of IS patients. M1 macrophages and activated mast cells were slightly increased in the IS group but had no significant difference compared to the normal control group (Figure 6(b)). Furthermore, we analyzed the correlation among the immune cells and found that monocytes were significantly positively correlated to M2 macrophages and significantly negatively correlated to activated NK cells and activated mast cells (Figure 7(a)). Moreover, we analyzed the correlation between the immune cells and the eight variables related to IS and found that STT3A was significantly negative-correlated to follicular helper T cells, activated NK cells and resting dendritic cells (Figure 7(b)).

Details are in the caption following the image
Details are in the caption following the image
Details are in the caption following the image
Details are in the caption following the image

3.6. Verification of the Diagnostic Efficacy of the Key miRNAs

GSE117064 were included in this study as the verification series to validate the diagnostic efficacy of the above three miRNAs. Has-miR-16-5p was more advantageous for diagnosing stroke than the other two miRNAs, as shown in Figure 8.

Details are in the caption following the image

4. Discussion

Stroke causes great burden on human health and the economy. Although prominent improvements in the early diagnosis and treatment of IS in the past decade, it is still a leading cause of death and disability. Thus, identifying new biomarkers for the early diagnosis of IS is essential. Recently, serum glutamic oxaloacetic transaminase is reported to may be utilized as predictor in detection of early neurological deterioration in acute IS [29]. Here, we first used the GEO data set to detect the differentially expressed exosomal miRNAs associated with IS and identified three miRNAs (hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p) intersected with those differentially expressed miRNAs from freshly removed human stroke brain tissue [25]. Among the predicted target genes of the three differentially expressed exosomal miRNAs, 25 mRNAs were obtained by intersecting with differentially expressed genes from GSE22255. Then, we used LASSO algorithm to identify eight key genes related to IS, and further analyzed the independent prediction ROC curve. Subsequently, we analyzed the immune cell patterns in the peripheral bloods of IS patients and the correlation between the immune cells and the eight key genes as potential biomarkers for IS.

Previous studies have reported the significance of the miRNAs, which were identified in our study. hsa-miR-15b-5p is highly expressed in the plasma of Alzheimer’s disease (AD) patients, and could distinguish AD patients from normal controls [30, 31]. Besides, hsa-miR-15b-5p in the aqueous humour of patients with diabetic macular oedema shows a fold change greater than –50 in log2 values, compared to the control group [32]. In this study, we firstly identified hsa-miR-15b-5p is highly expressed in the exosomes of IS patients. Recently, hsa-miR-15b-5p is found to regulate the proliferation and apoptosis of human vascular smooth muscle cells [33]. However, the specific mechanism of action of hsa-miR-15b-5p in stroke is unclear, and needs further investigation. miR-16-5p is found to be highly expressed in the in serum and plasma of patients with colorectal cancer [34], and in the feces of patients with precancerous lesions [35]. Besides, hsa-miR-16-5p may be a good candidate for identification of predictive biomarkers of duloxetine response in patients with major depressive disorder who are responsive to duloxetine treatment [36], suggesting that hsa-miR-16-5p may play important roles in the nervous system disease. Consistently, we also found hsa-miR-16-5p is highly expressed in the serum of IS patients, and the specific role of hsa-miR-16-5p in IS needs further investigation. Hsa-miR-184 has been proposed as a biomarker for several cancers, including non-small cell lung, uterine corpus endometrial carcinoma, and oral squamous cell carcinoma [3739], and brain-enriched hsa-miR-184 is downregulated in older adults with major depressive disorder [40]. Here, we identified that hsa-miR-184 is highly expressed in the serum of IS patients. Moreover, the co-regulated genes of the above three miRNAs were enriched in the N-glycan biosynthesis, nicotinate and nicotinamide metabolism, and pentose phosphate pathways. Interestingly, N-glycosylated immunoglobulin G has been shown to be associated with IS [41], and plasma N-glycans could as emerging biomarkers of cardiometabolic risk [42]. How the three miRNAs regulating N-glycan biosynthesis to affect the IS development would be explored in our following studies, and it could be a very interesting area.

Peripheral immune cells interplay with the central nervous system, and play important roles in the brain development, and in the process of IS injury [43, 44]. The immune system is rapidly activated after IS, and peripheral immune cells migrate and infiltrate across the blood–brain barrier into the ischemic region to affect infarction progression and prognosis. Leukocytes are found to aggregate in the ischemic region of MCAO models as early as 30 min after occlusion [45]. Yilmaz et al. fond that CD4+ and CD8+ T cells are distributed in the brain tissue 24 h after IS onset, and act detrimental effects on post-ischemic cerebral immune responses [46]. In this study, we analyzed the different immune cell patterns of the peripheral bloods between IS patients and normal controls from GSE22255, and found M0 macrophages and resting mast cells were significantly decreased in the IS group, and pro-inflammatory M1 macrophages, and activated mast cells were slight increased, suggesting that the inflammatory responses were rapidly activated after stroke. Our result is consistent with recent study that CD11b + CD45+ and CD11b + Ly6G- monocytes and macrophages were greatly increased 3 days after cardiac arrest and resuscitation [47]. Mast cells are rapidly activated and release TNF-α and histamine to aggravate brain damage after IS [48, 49]. Among the eight key genes potentially targeted by the above three miRNAs identified in our study, STT3A, a catalytic subunit of the oligosaccharyltransferase, increases amyloid-β production by promoting N-glycosylation in the pathogenesis of Alzheimer’s disease [50]. Besides, the expression level of STT3A was found to be negatively related to the biomarker expressions of M1 macrophages in breast cancer [51], indicating that STT3A may be involved in the regulating macrophage activation. Although the mechanism of regulating macrophages or mast cells has been extensively study, whether hsa-miR-15b-5p/hsa-miR-184/hsa-miR-16-5p-STT3A axis is involved in the regulating macrophages or mast activation in IS need further investigation.

This study has some limitations. For example, our analytical data are derived from public database with relatively small sample sizes. Second, important analysis results need to be further validated with clinical samples. Further large-scale basic studies can be carried out to verify the conclusions of this study.

5. Conclusions

We for the first time conducted a comprehensive bioinformatics analysis and identified three serum exosomal miRNAs (hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p), which may be involved in affecting the peripheral immune cell patterns of IS patients and might serve as promising diagnostic biomarkers. However, the specific pathogenesis and molecular targets still need to be further confirmed through molecular experiments.

Conflicts of Interest

There are no conflicts of interest to disclose for all authors.

Acknowledgments

The results of this study were in part derived from the GEO databases (GSE199942, GSE22255, GSE117064 and GSE16561) and from the PMC8702168. This study was supported by the Science and Technology Planning Project of Guangzhou (202102020119, and 202201020514), Guangdong Medical Research Foundation (A2021399), and Science Foundation of Guandong Second Provincial General Hospital (3D-B2020010).

    Data Availability

    The data analyzed in the present study are publicly available on the GEO data sets database. The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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