CircRNA_0004104 Participates in Regulating Trophoblast Invasion, Migration and Oxidative Stress in Pre‐eclampsia Through microRNA‐198

Pre‐eclampsia (PE) is a pregnancy‐related disorder characterized by hypertension and proteinuria, growing evidence have indicated that dysregulated circRNAs participates in regulation of PE pathogenesis. CircRNA_0004104 (circ_0004104) was recently proven to play important roles in atherosclerosis and coronary artery disease, and previous GSE96985 microarray showed that circ_0004104 was aberrantly expressed in PE, we hypothesized that circ_0004104 might be related to PE. This study aims to investigate the relationship between circ_0004104 expression and PE severity, and to evaluate its role and related mechanism in trophoblast cellular behaviors. Real‐time quantitative polymerase chain reaction analysis of circ_0004104 expression in plasma and placenta samples from 60 PE patients (including 21 mind PE and 39 severe PE) and 60 healthy pregnancy (HP) revealed that circ_0004104 levels were significantly downregulated in severe PE compared to mind PE and HP. Receiver operating characteristic curves found that the area under curve (AUC) of plasma circ_0004104 for distinguishing severe PE form mind PE was 0.835, the AUC increased to 0.862 when combined with sFlt‐1/PlGF ratio. In vitro transwell assays revealed that circ_0004104 knockdown suppressed HTR8/SVneo cell invasion and migration, and enhanced the levels of reactive oxidative stress and malondialdehyde, whereas ectopic expression of circ_0004104 produced the opposite effects. RNA immunoprecipitation and luciferase reporter assays verified that circ_0004104 could serve as a sponge of miR‐198. Additionally, rescue experiment confirmed that miR‐198 silencing counteracted the effect of circ_0004104 knockdown on the biological functions of HTR8/SVneo cells. Our data demonstrated that decreased circ_0004104 could be a new biomarker for PE severity, and circ_0004104 promoted trophoblast cell invasion and migration and declined oxidative stress by sponge of miR‐198, thereby blocking PE progression.