Objective: To investigate the circulating immune circRNA-miRNA-mRNA axis in patients with ischemic stroke (IS), and to find molecular targets for the treatment of IS. Methods: The GSE16561, GSE195442 datasets were retrieved from the GEO database, using the R software or the GEO2R tool to find the differentially expressed genes ,circRNAs between the blood of ischemic stroke patients and normal controls. A protein-protein interaction (PPI) network was constructed through the STRING database, visualized with Cytoscape 3.9.1, and genes with high scores were selected using the Betweenness Centrality in CytoNCA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the top 15 differential genes with high scores. Thereafter, the miRNA-mRNA regulatory network was constructed by predicting the target miRNAs according to the mirTargets 2.0 database. The differentially expressed circRNAs in IS patients were selected using the GEO2R tool, Combined with literature selected significant differences circRNAs and what has been validated by PCR, the circRNA-miRNA regulatory network was constructed using Circular RNA Interactome. The intersection of the two regulatory networks predicted the possible regulatory networks in the IS, and further constructed the immune-related circRNA-miRNA-mRNA axis, Validation of the miRNAs in the immune-related circRNA-miRNA-mRNA axis using the GSE117064 dataset. Results: This study identified many transcription factors, genes including CD247, IL2RB, STAT1, and miRNAs including hsa-miR-892a, hsa-miR-938, hsa-miR-338-3p, and predicted seven possible immune-related circRNA-miRNA-mRNA axes, for example hsa_circ_0112036 - hsa-miR-892a - CD247, hsa_circ_0112036 - hsa-miR-892a - IL2RB, hsa_circ_0093708 - hsa-miR-1248 - STAT1. Conclusion: The hsa _ circ _ 0112036 may serve as a molecular sponge of hsa-miR-892a, hsa-miR-938, hsa-miR-1276, hsa-miR-1208, and hsa-miR-338-3p to regulate the progression of IS. Regulating IS progression as hsa _ circ _ 0093708 may act as a molecular sponge for hsa-miR-1248.
[1] Walter K.What is acute ischemic stroke [J].Jama,2022,327(9): 885.
[2] Herpich F,Rincon F.Management of acute ischemic stroke [J].Crit Care Med,2020,48(11): 1654-1663.
[3] Chalela JA,Kidwell CS,Nentwich LM,et al.Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison [J].Lancet,2007,369(9558): 293-298.
[4] von Kummer R,Allen KL,Holle R,et al.Acute stroke: usefulness of early CT findings before thrombolytic therapy [J].Radiology,1997,205(2): 327-333.
[5] Yang J,He W,Gu L,et al.CircFOXP1 alleviates brain injury after acute ischemic stroke by regulating STAT3/apoptotic signaling [J].Transl Res,2023,257: 15-29.
[6] 鞠馨瑶,李潇,俞倩,等.环状RNA与缺血性脑卒中相关研究现状 [J].中国临床药理学杂志,2022,38(01): 72-75.
[7] Tiedt S,Prestel M,Malik R,et al.RNA-Seq identifies circulating miR-125a-5p,miR-125b-5p,and miR-143-3p as potential biomarkers for acute ischemic stroke [J].Circ Res,2017,121(8): 970-980.
[8] Yang J,Hao J,Lin Y,et al.Profile and functional prediction of plasma exosome-derived circRNAs from acute ischemic stroke patients [J].Front Genet,2022,13: 810974.
[9] Vos T,Lim S S,Abbafati C,et al.Global burden of 369 diseases and injuries in 204 countries and territories,1990-2019: a systematic analysis for the Global Burden of Disease Study 2019 [J].Lancet,2020,396(10258): 1204-1222.
[10] Burlacu CC,Ciobanu D,Badulescu AV,et al.Circulating microRNAs and extracellular vesicle-derived microRNAs as predictors of functional recovery in ischemic stroke patients: a systematic review and meta-analysis [J].Int J Mol Sci,2022,24(1): 251
[11] Memczak S,Jens M,Elefsinioti A,et al.Circular RNAs are a large class of animal RNAs with regulatory potency [J].Nature,2013,495(7441): 333-338.
[12] Hansen TB,Jensen TI,Clausen BH,et al.Natural RNA circles function as efficient microRNA sponges [J].Nature,2013,495(7441): 384-388.
[13] Pei L,Xu X,Yuan T.Circ_0101874 overexpression strengthens PDE4D expression by targeting miR-335-5p to promote neuronal injury in ischemic stroke [J].J Stroke Cerebrovasc Dis,2022,31(12): 106817.
[14] Chen W,Zhang Y,Yin M,et al.Circular RNA circPRDX3 mediates neuronal survival apoptosis in ischemic stroke by targeting miR-641 and NPR3 [J].Brain Res,2022,1797: 148114.
[15] Wang XZ,Li S,Liu Y,et al.Construction of circRNA-mediated immune-related ceRNA network and identification of circulating circRNAs as diagnostic biomarkers in acute ischemic stroke [J].J Inflamm Res,2022,15: 4087-4104.
[16] Cao S,Zeng Y,Chen M,et al.Integrated analysis of immune-related circRNA-miRNA-mRNA regulatory network in ischemic stroke [J].Front Neurol,2022,13: 889855.
[17] Li W,Pang H,Xie L.Depletion of circ_0006459 protects human brain microvascular endothelial cells from oxygen-glucose deprivation-induced damage through the miR-940/FOXJ2 pathway [J].Transpl Immunol,2023: 101780.
[18] Bai X,Liu X,Wu H,et al.CircFUNDC1 knockdown alleviates oxygen-glucose deprivation-induced human brain microvascular endothelial cell injuries by inhibiting PTEN via miR-375 [J].Neurosci Lett,2022,770: 136381.
[19] Yang J,He W,Gu L,et al.CircUSP36 attenuates ischemic stroke injury through the miR-139-3p/SMAD3/Bcl2 signal axis [J].Clin Sci (Lond),2022,136(12): 953-971.
[20] Tan L,Wang L,Liu J,et al.Circvrk1 downregulation attenuates brain microvascular endothelial cell damage induced by oxygen-glucose deprivation through modulating the miR-150-5p/MLLT1 axis [J].Exp Brain Res,2023,241(3): 781-791.
[21] Li L,Zhang D,Yao W,et al.Ligustrazine exerts neuroprotective effects via circ_0008146/miR-709/Cx3cr1 axis to inhibit cell apoptosis and inflammation after cerebral ischemia/reperfusion injury [J].Brain Res Bull,2022,190: 244-255.
[22] Chen ZQ,Zuo XL,Cai J,et al.Hypoxia-associated circPRDM4 promotes immune escape via HIF-1α regulation of PD-L1 in hepatocellular carcinoma [J].Exp Hematol Oncol,2023,12(1): 17.
[23] Peng W,Ye L,Xue Q,et al.Silencing of circCRIM1 drives IGF2BP1-mediated NSCLC immune evasion [J].Cells,2023,12(2): 273.
[24] Ying K,Chen J,Fu Z,et al.FAS-mediated circRNA-miRNA-mRNA crosstalk network regulates immune cell infiltration in cerebral infarction [J].J Mol Neurosci,2023,73(2-3): 117-128.
[25] Lv J,Li K,Yu H,et al.HNRNPL induced circFAM13B increased bladder cancer immunotherapy sensitivity via inhibiting glycolysis through IGF2BP1/PKM2 pathway [J].J Exp Clin Cancer Res,2023,42(1): 41.
[26] Zhang P,Zhao L,Li H,et al.Novel diagnostic biomarkers related to immune infiltration in Parkinson's disease by bioinformatics analysis [J].Front Neurosci,2023,17: 1083928.
[27] Xue X,Wang J,Fu K,et al.The role of miR-155 on liver diseases by modulating immunity,inflammation and tumorigenesis [J].Int Immunopharmacol,2023,116: 109775.
