circSKA3 acts as a sponge of miR‐6796‐5p to be associated with outcomes of ischemic stroke by regulating matrix metalloproteinase 9 expression

Abstract

Background and purpose This study was undertaken to screen the circular RNAs (circRNAs) influencing matrix metalloproteinase 9 (MMP9) through the competing endogenous RNA (ceRNA) network and evaluate the prognostic value of these circRNAs for acute ischemic stroke. Methods A total of 220 ischemic stroke patients and 62 healthy subjects were included in this study. RNA was isolated from blood collected in PAXgene tubes. Illumina sequencing, quantitative real‐time polymerase chain reaction (qRT‐PCR) validation, and luciferase reporter assay were explored to construct and verify the existence of a circRNA–microRNA (miRNA)–matrix metalloproteinase–9 (MMP9) network. The 215 ischemic stroke patients were recruited in a prognostic cohort. They were prospectively followed up for 3 months after stroke onset, and a poor functional outcome was defined as a major disability or death. Results After Illumina sequencing, six circRNAs were predicted to bind miRNAs and then regulate MMP9 messenger RNA (mRNA). qRT‐PCR showed that only circSKA3 was significantly increased in ischemic stroke patients compared to healthy controls and positively associated with MMP9 mRNA expression. Luciferase reporter assay further verified a direct interaction between circSKA3, MMP9, and hsa‐miR‐6796‐5p. Patients in the top tertile of circSKA3 had a 2.672‐fold (p < 0.05) risk of poor functional outcome, compared with those in the bottom tertile (p for trend = 0.016). The outcome was predicted by circSKA3 with area under the receiver operating characteristic curve at 0.614 (p = 0.004). Conclusions circSKA3 functioned as a ceRNA for hsa‐miR‐6796‐5p to aggravate the progression of ischemic stroke via targeting MMP9. Baseline circSKA3 was positively associated with poor outcomes of ischemic stroke. circSKA3 may be a potential biomarker or therapeutic target in ischemic stroke.

A crosstalk between circular RNA, microRNA, and messenger RNA in the development of various brain cognitive disorders

“…The crosstalk between circRNA, miRNA, and mRNA (or proteins) through one or more circRNA–miRNA–mRNA networks indicates the complicated and dynamic mechanisms of brain cognitive disorders including AD (Zhao et al, 2016 ; Lu et al, 2019 ; Yang et al, 2019 ; Zhu et al, 2020 ; Li et al, 2022 ; Pan et al, 2022 ; Xu X. et al, 2022 ), PD (Kumar et al, 2018 ; Feng et al, 2020 ; Wang et al, 2021 ; Liu et al, 2022 ; Zhang et al, 2022 ), TBI (Chen et al, 2019 ; Li H. et al, 2020 ; Huang X. J. et al, 2022 ; Zheng et al, 2022 ), stroke (Bai et al, 2018 ; Han et al, 2018 ; Zhou et al, 2021 ; Guo et al, 2022 ; Huang et al, 2022 ; Xu T. et al, 2022 ; Yang H. et al, 2022 ; Yang J. et al, 2022 ), and POND (Gao et al, 2020 ) ( Table 1 ). In summary, circRNAs act as sponging-like roles in transcription and posttranscription in the novel regulation processes of gene expression.…”

“…Overexpression of circ_0000831 is sufficient to inhibit neuroinflammation and vertigo in cerebral ischemia through a miR-16-5p-dependent mechanism (Huang et al, 2022 ). circSKA3, in an area under the ROC curve of 0.614 (95% CI: 0.546–0.680) in predicting clinical outcomes of patients with AIS, acts as a sponge of miR-6796-5p by regulating the expression of matrix metalloproteinase 9 (Xu T. et al, 2022 ). Hypoxic pretreated adipose-derived stem cell (ADSC) exosome improves cognitive function by decreasing neuronal damage and shifting microglia from an M1 to M2 phenotype in the hippocampus of AIS via circRps5/miR-124-3p/SIRT7 axes (Yang H. et al, 2022 ).…”

“…A lot of studies indicate that the crosstalk between circRNAs, miRNAs, and mRNA can participate in many pathophysiological processes in the development of cerebral diseases (or abnormal conditions), such as Alzheimer's disease (AD) (Lu et al, 2019 ; Li et al, 2022 ), Parkinson's disease (PD) (Wang et al, 2021 ; Liu et al, 2022 ), traumatic brain injury (TBI) (Huang X. J. et al, 2022 ; Zheng et al, 2022 ), stroke (Dai et al, 2021 ; Xu T. et al, 2022 ), and postoperative neurocognitive disorder (POND) (He et al, 2021 ; Wu et al, 2021 ; Zhang M. X. et al, 2022 ). However, they have failed to manage the aforementioned brain cognitive disorders with effective therapeutics and to uncover largely unknown underlying mechanisms.…”

The regulatory roles of circular RNAs via autophagy in ischemic stroke

“…Circ cGLIS3 ( 46 ), circRNA TLK1 ( 136 ), circPHC3 ( 45 ), circFUNDC1 ( 44 ), and circCDC14A ( 43 ) contribute to cell death by activating apoptosis. Overexpression of circ HIPK2 ( 56 ) and circSKA3 ( 137 ) aggravates neuronal injuries.…”

Integrated Analysis of Immune-Related circRNA-miRNA-mRNA Regulatory Network in Ischemic Stroke

“…A recent study reported that hsa_circ_0045932 (circUSP36) attenuates ischemic stroke injury through the miR-139-3p/SMAD3/Bcl2 signaling axis ( 19 ). Xu et al ( 20 ) revealed that circSKA3 could compete for binding hsa-miR-6796-5p and thereby regulates MMP9 to promote ischemic stroke progression. However, there remain numerous dysregulated circRNAs whose roles in IS have not been reported.…”