Identification of mRNA-, circRNA- and lncRNA- Associated ceRNA Networks and Potential Biomarkers for Preeclampsia From Umbilical Vein Endothelial Cells

Abstract

ObjectiveThe etiology and pathogenesis of preeclampsia (PE) remain unclear, and ideal biomarkers for the early detection of PE are scarce. The involvement of the competing endogenous RNA (ceRNA) hypothesis in PE is only partially understood. The present study aimed to delineate a regulatory network in PE comprised of messenger RNAs (mRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) via ceRNA profiles from human umbilical vein endothelial cells (HUVECs) to further reveal the pathogenesis of PE and potential biomarkers.MethodsDifferentially expressed mRNAs, circRNAs, and lncRNAs were detected in HUVECs from early onset preeclampsia (EOPE) cases (n = 4) and normal pregnancies (n = 4) by microarray analysis. Bioinformatics analysis was performed to systematically analyze the data, and a relevant ceRNA network was constructed. RNAs (ANGPT2, LIPG, hsa_circ_0025992, hsa_circ_0090396, hsa_circ_0066955, hsa_circ_0041203, hsa_circ_0018116, lnc-C17orf64-1:1, lnc-SLC27A2-2:1, and lnc-UEVLD-5:1) were validated by quantitative real-time PCR (qRT-PCR) in 10 pairs of HUVECs and placental tissues from PE patients and normal pregnancies. Furthermore, expression of hsa_circ_0025992 was detected in maternal peripheral blood samples from PE patients (n = 24) and normal pregnancies (n = 30) to confirm its potential as a novel biomarker. The receiver operating characteristic (ROC) curve was applied to analyze its diagnostic value.ResultsCompared with HUVECs from normal pregnancies, HUVECs from EOPE cases had 33 differentially expressed mRNAs (DEmRNAs), 272 DEcircRNAs, and 207 DElncRNAs. GO and KEGG analyses of the DERNAs revealed the biological processes and pathways involved in PE. Based on the microarray data and the predicted miRNAs, a ceRNA network was constructed with four mRNAs, 34 circRNAs, nine lncRNAs, and 99 miRNAs. GO and KEGG analyses of the network reinforced the crucial roles of metabolic disorders, the p53 and JAK/STAT signaling pathways in PE. In addition, ROC analysis indicated that hsa_circ_0025992 could be used as a novel biomarker for PE.ConclusionA novel ceRNA network was revealed in PE, and the potential of hsa_circ_0025992 to serve as a new biomarker was confirmed.

Bone marrow stromal cell antigen 2(BST2) suppresses the migration and invasion of trophoblasts in preeclampsia by downregulating matrix metallopeptidase 2(MMP2)

“…Two pieces of placental tissue (approximately 1 cm 3 each) were dissected from the maternal surface of the placentas (away from the umbilical cord attachment area, avoiding bleeding and calcification). Placental tissues were separated and stored at −80°C [ 24 ]. Preeclampsia was defined as hypertension with proteinuria (urinary protein > 300 mg/24 h) that occurred after 20 weeks of gestation [ 4 ].…”

“…Our previous study demonstrated that BST2 expression was differentially expressed in human umbilical vein endothelial cells (HUVECs) between normal and PE pregnancies [ 24 ]. However, the expression of BST2 in the placenta of pregnant women with PE and its specific mechanism of action have not yet been reported.…”

Significance of Sex Differences in ncRNAs Expression and Function in Pregnancy and Related Complications

“…It is usually diagnosed after week 20 of gestation and is characterized by maternal hypertension and proteinuria [ 14 ]. An increasing number of studies have been investigating PE etiopathogenesis, showing that ncRNAs, especially miRNAs [ 14 ], circRNAs [ 94 , 95 , 96 ], and lncRNAs [ 44 ] detectable in both maternal placenta and plasma, have a crucial role in endothelial angiogenic function and placentation [ 97 , 98 , 99 ].…”

Circulating noncoding RNAs as early predictive biomarkers in preeclampsia: A diagnostic meta-analysis

“…Subsequently, we assessed the full texts of the remaining 48 articles and excluded 34 studies based on the exclusion criteria, including 7 not studies on circulating ncRNAs, 8 without clinical data to make a 2 × 2 contingency table and 8 studies that used ncRNAs for diagnosis. In total, 14 studies were ultimately included in this study [14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The selection process ow chart of our study is presented in Fig.…”