Circulating Circular RNAs as Biomarkers for the Diagnosis and Prediction of Outcomes in Acute Ischemic Stroke

Zuo, Lei; Zhang, Lin; Zu, Juan; Wang, Zan; Han, Bing; Chen, Biling; Cheng, Mengjing; Ju, Minzi; Li, Mingyue; Shu, Guofang; Yuan, Mengqin; Jiang, Wei; Chen, Xufeng; Yan, Fuling; Zhang, Zhijun; Yao, Honghong

doi:10.1161/strokeaha.119.027348

Cited by 123 publications

(111 citation statements)

References 8 publications

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“…Our results also support previous findings that circRNAs can serve as novel diagnostic biomarkers and promising therapeutic targets for IS 26,[36][37][38][39] . In the present study, based on the results of bioinformatic analyses, three of the top ten significantly DE circRNAs were selected for PCR validation in AIS patients and healthy controls.…”

Section: Discussionsupporting

confidence: 91%

Expression profile and bioinformatics analysis of circular RNAs in acute ischemic stroke in a South Chinese Han population

Chen

et al. 2020

Sci Rep

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Recent studies have found that circular RNAs (circRNAs) play crucial roles not only in the normal growth and the development of different tissues and organs but also in the pathogenesis and progression of various disorders. However, the expression patterns and the function of circRNAs in acute ischemic stroke (AIS) in the South Chinese Han population are unclear. In the present study, RNA sequencing (RNA-seq) data was generated from 3 AIS patients and 3 healthy controls. The circRNAs were detected and identified by CIRI2 and Find_circ software. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were used to detect the expression of circRNAs. Meanwhile, the potential diagnostic value of the selected circRNAs for AIS was assessed by generating receiver operating characteristic (ROC) curve with area under curve (AUC). The bioinformatic analysis of the host genes of differentially expressed (DE) circRNAs was performed by gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, KOBAS for pathway analysis and regulatory network analysis. miRNA-circRNA and miRNA-mRNA interactions were predicted by using TargetScan, miRanda and starBase. CircRNA-miRNA-mRNA interaction networks were created with Cytoscape. Our result showed that there were 2270 DE circRNAs between AIS patients and healthy controls. Among them, 659 were found upregulated and 1611 were downregulated. Bioinformatic analysis showed that the DE circRNAs were related to the following biological processes: endocytosis, energy metabolism, apoptosis, FoxO signaling pathway, platelet activation, neurotrophin signaling pathway and VEGF signaling pathway, which may be associated with the pathological of AIS. Three randomly selected circRNAs were successfully validated by qRT-PCR. The results show that hsa_circ_0005548 was significantly upregulated, while hsa_circ_0000607 and hsa_circ_0002465 were significantly downregulated in AIS. Furthermore, the AUC values for hsa_circ_005548, hsa_circ_0000607 and hsa_circ_0002465 were 0.51, 0.75 and 0.69, respectively, suggesting that hsa_circ_0000607 and hsa_circ_0002465 could be potential biomarkers for AIS. In addition, Bcl2 was predicted to be a direct target of miR-337-3p, and hsa_circRNA_0000607 was predicted to act as a sponge for miR-337-3p. Thus, hsa_circ_0000607 may be involved in AIS by regulating the miR-337-3p/ Bcl2 axis. Collectively, our findings indicate that numerous dysregulated circRNAs may play pivotal functional roles in AIS and hsa_circ_0000607 may play a crucial role in the pathogenesis and progression of AIS by regulating the miR-337-3p/Bcl2 axis. Stroke is one of the leading causes of death and a major cause of long-term disability worldwide. Approximately 87% of all stroke cases are ischemic stroke (IS) 1. Although major progress in the diagnosis and treatment of acute ischemic stroke (AIS) has been reported in recent years, the mortality and long-term disability rates of IS are still high. Moreover, recombinant tissue plasminogen activa...

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Section: Discussionsupporting

confidence: 91%

Expression profile and bioinformatics analysis of circular RNAs in acute ischemic stroke in a South Chinese Han population

Chen

et al. 2020

Sci Rep

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“…As reported in our previous research, circFUNDC1 has been verified to be important biomarker in stroke diagnosis and prognosis [12]. Our present study furtherly illustrated that the incidence of SAI increased with increasing level of circFUNDC1.…”

Section: Discussionsupporting

confidence: 89%

“…As for the origins of elevated circFUNDC1 in plasma, our previous research has shown that no significant increase of circFUNDC1 levels was found in platelets and granulocytes of AIS patients compared with healthy controls [12]. However, the current study demonstrated that circFUNDC1 was enriched in platelets meaning that platelets might be important origins of circFUNDC1 in plasma.…”

Section: Discussioncontrasting

confidence: 62%

Circular RNA FUNDC1 improves prediction of stroke associated infection in acute ischemic stroke patients with high risk

Zuo

Cai

et al. 2020

Bioscience Reports

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Identifying those patients who were at high risk of stroke associated infection (SAI) for preventive antibiotic therapy was imperative for patients’ benefits, thus improving prediction of SAI was critical for all acute ischemic stroke (AIS) patients. Circular RNA FUNDC1 (circFUNDC1) has been reported to be the diagnosis and prognosis biomarker of AIS. Therefore, the present study aimed to figure out whether circFUNDC1 could be the potential predictor of SAI that could help to guide preventive treatment. In total, 68 patients were included in the study, 26 of which had infection and 42 without. Copy number of circFUNDC1 in plasma were quantified by quantitative real-time polymerase chain reaction (qPCR). Platelet spike-in experiment and correlation analysis were conducted to explore possible origins of circFUNDC1 in plasma. A significantly elevated level of circFUNDC1 was found in SAI patients compared with not infected AIS patients (P=0.0258). Receiver operating characteristic (ROC) curves demonstrated the prediction significance of circFUNDC1, with the area under the curve (AUC) at 0.6612 and sensitivity, specificity at 69.23%, 61.90% respectively in predicting SAI. Then, when adding circFUNDC1 in the risk model, the AUC increased from 0.7971 in model A to 0.8038 in model B. Additionally, positive correlation was observed between circFUNDC1 level and neutrophils counts. WBC and neutrophil ratios were significantly elevated in SAI patients compared with non-SAI patients. Therefore, circFUNDC1 could be used to construct a risk model for the prediction of SAI that is beneficial for AIS patients’ preventive treatment.

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“… 31 , 32 , 33 Furthermore, certain circRNAs have been proposed as transcriptional and translational regulators in pathological aspects of several cerebrovascular diseases. 34 , 35 Previous studies have shown that the circRNA DLGAP4 ameliorates ischemic stroke. 36 However, the role of the circRNA circUCK2 has not been evaluated in ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

Chen

Wang

Feng

et al. 2020

Molecular Therapy - Nucleic Acids

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Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various central nervous system diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Herein, we uncovered the function and underlying mechanism of the circRNA UCK2 (circUCK2) in ischemia stroke. The oxygen-glucose deprivation model in HT-22 cells was used to mimic ischemia stroke in vitro . Neuronal viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assays and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining, respectively. Middle cerebral artery occlusion was conducted to evaluate the function of circUCK2 in mice. The levels of circUCK2 were significantly decreased in brain tissues from a mouse model of focal cerebral ischemia and reperfusion. Upregulated circUCK2 levels significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. circUCK2 reduced oxygen glucose deprivation (OGD)-induced cell apoptosis by regulating transforming growth factor β (TGF-β)/mothers against decapentaplegic homolog 3 (Smad3) signaling. Furthermore, circUCK2 functioned as an endogenous miR-125b-5p sponge to inhibit miR-125b-5p activity, resulting in an increase in growth differentiation factor 11 (GDF11) expression and a subsequent amelioration of neuronal injury. Consequently, these findings showed that the circUCK2/miR-125b-5p/GDF11 axis is an essential signaling pathway during ischemia stroke. Thus, the circRNA circUCK2 may serve as a potential target for novel treatment in patients with ischemic stroke.

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Circulating Circular RNAs as Biomarkers for the Diagnosis and Prediction of Outcomes in Acute Ischemic Stroke

Cited by 123 publications

References 8 publications

Expression profile and bioinformatics analysis of circular RNAs in acute ischemic stroke in a South Chinese Han population

Expression profile and bioinformatics analysis of circular RNAs in acute ischemic stroke in a South Chinese Han population

Circular RNA FUNDC1 improves prediction of stroke associated infection in acute ischemic stroke patients with high risk

RETRACTED: Overexpression of circRNA circUCK2 Attenuates Cell Apoptosis in Cerebral Ischemia-Reperfusion Injury via miR-125b-5p/GDF11 Signaling

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