Abstract
BackgroundPreeclampsia is a severe disease in pregnant women, which is primarily managed by early screening and prevention. Circular RNAs (circRNAs) have increasingly been shown to be important biological regulators involved in numerous diseases. Further, increasing evidence has demonstrated that circRNAs can be used as diagnostic biomarkers. This study was conducted to evaluate the potential of circCRAMP1L, previously identified to be downregulated in preeclampsia, as a novel biomarker for predicting the development of preeclampsia.MethodsWe measured the expression of circCRAMP1L, which is reportedly relevant to trophoblast physiology, in plasma samples from 64 patients with preeclampsia and 64 age-, gestational age-, and body mass index-matched healthy pregnant women by qRT-PCR. MTT proliferation and transwell invasion assays revealed the biological role of circCRAMP1L in preeclampsia pathogenesis. RNA immunoprecipitation and dual-luciferase reporter assays clarified the mechanism underlying the biological function of circCRAMP1L in TEV-1 cells.ResultscircCRAMP1L circulating levels were significantly lower in patients with preeclampsia (2.66 ± 0.82, △Ct value) than in healthy pregnant women (3.95 ± 0.67, △Ct value, p < 0.001). The area under the receiver operating characteristic curve for circCRAMP1L was 0.813. Univariate and multivariate analyses identified circCRAMP1L as an independent predictor of preeclampsia. Furthermore, when circCRAMP1L was utilised in combination with its target protein macrophage stimulating protein (MSP), the predictive performance increased, with an area under the receiver operating characteristic curve of 0.928 (95% CI 0.882–0.974), 80.0% sensitivity, and 80.0% specificity. The in vitro results indicated that circCRAMP1L regulates cell proliferation, and invasion via MSP and RON proteins. We investigated the molecular mechanisms of these effects. In vitro, relative to the control group, circCRAMP1L overexpression significantly enhanced cell proliferation; furthermore, trophoblast cell invasion increased proportionally with circCRAMP1L expression. RNA immunoprecipitation and luciferase reporter gene illustrated that circCRAMP1L participated in regulation of trophoblast cell by regulating MSP.ConclusionReduced plasma levels of circCRAMP1L may be associated with an increased risk of preeclampsia, and circCRAMP1L may be a novel biomarker of preeclampsia risk.
Highlights
Preeclampsia is a severe disease in pregnant women, which is primarily managed by early screening and prevention
The theory holds that obstruction of the trophoblast differentiation phenotype during placenta formation leads to inadequate invasion and poor spiral artery remodelling, resulting in vascular endothelial cell damage, hypertension, and urinary protein in patients [6, 7]
Through bioinformatics prediction and preexperiments, we found that circCRAMP1L can interact with macrophage stimulating protein (MSP)
Summary
Preeclampsia is a severe disease in pregnant women, which is primarily managed by early screening and prevention. Increasing evidence has demonstrated that circRNAs can be used as diagnostic biomarkers. Studies are urgently needed to clarify the pathogenesis of PE, improve effective early interventions, reduce the risk of PE, and lower the mortality of pregnant women and foetuses. The theory holds that obstruction of the trophoblast differentiation phenotype during placenta formation leads to inadequate invasion and poor spiral artery remodelling, resulting in vascular endothelial cell damage, hypertension, and urinary protein in patients [6, 7]. The main pathological manifestation of the placenta in patients with PE is that trophoblasts invade the endometrium too shallowly and only reach the decidual layer, providing experimental evidence for this theory [8]
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