Silencing of circCDC14A prevents cerebral ischemia‐reperfusion injury via miR‐23a‐3p/CXCL12 axis

Abstract

Ischemic stroke is one of the main causes of death and disability. Circular RNAs (circRNAs) have received extensive attention in the pathogenesis of ischemic stroke. Here, we evaluated the role of circCDC14A in cerebral ischemia-reperfusion (CI/R) injury in vivo and in vitro. The expression of circCDC14A was significantly upregulated in the middle cerebral artery occlusion (MCAO) model and oxygen and glucose deprivation/reoxygenation (OGD/R)-treated HT22 cells. Knockdown of circCDC14A suppressed the cell viability reduction caused by OGD/R, as well as cell damage and apoptosis. Mechanistically, circCDC14A acted as a sponge for miR-23a-3p and promoted the expression of chemokine stromal-derived factor-1 (CXCL12) by negatively regulating miR-23a-3p.Rescue experiments further confirmed that miR-23a-3p inhibitor or circCDC14Aoverexpression vectors blocked the beneficial effects of circCDC14A knockdown in OGD/R-induced HT22 cells. Moreover, knockdown of circCDC14A suppressed MCAOinduced cerebral infarction and neurological damage, as well as the brain tissue damage and neuronal apoptosis in vivo. Consistently, miR-23a-3p antagomir treatment abolished the cerebral protective effects of circCDC14A knockdown on MCAO mice. In conclusion, circCDC14A promoted CI/R injury by regulating the miR-23a-3p/CXCL12 axis, which suggested that circCDC14A may become a potential therapeutic target for CI/R injury.

Circular RNAs in organ injury: recent development

“…Traumatic brain injury circLphn3 downregulated Improved BBB integrity and promoted inflammatory response [43] circLrp1b downregulated Inhibits inflammatory response [45] circHtra1 upregulated Inhibits cell proliferation and promotes cell apoptosis [46] Ischemia/reperfusion injury circCTNNB1 downregulated Improves BBB integrity and promotes cell proliferation [50] circFOXO3 upregulated Promotes autophagy and maintains BBB integrity [51] circCCDC9 downregulated Improves BBB integrity [52] circUCK2 downregulated Inhibits cell proliferation and promotes cell apoptosis [53] circCDC14A upregulated Promotes cell proliferation and migration [56] circUSP36 downregulated Inhibits cell apoptosis and promoted cell proliferation [31] Spinal cord Spinal cord injury circHIPK3 downregulated Inhibits cell proliferation and promotes cell apoptosis [60] circRNA_7079 upregulated Promotes inflammatory response [63] circRNA_2960 upregulated Promotes inflammatory response and inhibits cell apoptosis [65] Visceral organ…”

“…Huo et al identified circ-CDC14A as significantly upregulated during OGD/R induced I/RI condition in HT22 cells. Through sponging miR-23a-3p, circCDC14A can positively regulate chemokine (C-X-C motif ) ligand 12 (CXCL12) expression level to promote cell proliferation and migration [56]. Further study by Yang et al also showed that an alternative circRNA-circUSP36-may also promote cell proliferation in ischemic stroke via a different axis.…”

The regulatory roles of circular RNAs via autophagy in ischemic stroke

“…Circ-HECTD1 ( 25 ) aggregates neuronal deficits by promoting astrocyte autophagy via the miR142-TIPARP axis. 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.…”

Circular RNA PUM1 performs as a competing endogenous RNA of microRNA-340-5p to mediate DEAD-box helicase 5 to mitigate cerebral ischemia-reperfusion injury

“…Circular RNAs (circRNAs), a group of non-coding RNAs with covalently closed-loop structures, are generated by back-splicing of eukaryotic exons without 5’-cap and 3’-polyA and are specifically expressed in tissues and cells [ 6 ]. Many studies have demonstrated that circRNAs are involved in the process of CI/R development, including circOGDH [ 7 ], circMEMO1 [ 8 ], and circCDC14A [ 9 ]. These circRNAs act as biomarkers in the CI/R process or regulate neuronal viability, apoptosis, inflammation and oxidative stress processes.…”