Potential regulatory network in the PSG10P/miR‐19a‐3p/IL1RAP pathway is possibly involved in preeclampsia pathogenesis

Abstract

Preeclampsia (PE), a pregnancy‐specific disorder, is a leading cause of perinatal maternal‐fetal mortality and morbidity. Impaired cell migration and invasion of trophoblastic cells and an imbalanced systemic maternal inflammatory response have been proposed as potential mechanisms of PE pathogenesis. Comparative analysis between PE placentas and normal placentas profiled differentially expressed miRNAs, lncRNAs, and mRNAs, including miR‐19a‐3p (miRNA), PSG10P (lncRNA), and IL1RAP (mRNA). This study was conducted to investigate their potential roles in PE pathogenesis. The expression of miR‐19a‐3p, PSG10P, and IL1RAP was examined in PE and normal placentas using RT‐qPCR. An in vitro experiment was performed in human trophoblast HET8/SVneo and TEV‐1 cells cultured in normoxic and hypoxic conditions. MiR‐19a‐3p targets were identified using Targetscan, miRanda, and PicTar analysis as well as luciferase reporter assays. The mouse model of PE was conducted using sFlt‐1 for in vivo tests. Lower levels of miR‐19a‐3p, but higher levels of PSG10P and IL1RAP were observed in PE placentas and the trophoblast cells in hypoxia. Luciferase reporter assays confirmed that PSG10P and IL1RAP were both direct targets of miR‐19a‐3p. Exposure to hypoxia inhibited cell viability, migration, and invasion of HET8/SVneo and TEV‐1 cells. Knocking out PSG10P and IL1RAP or overexpressing miR‐19a‐3p rescued the inhibition caused by hypoxia. In vivo experiments showed that IL1RAP promoted the expression of caspase‐3, a key apoptosis enzyme, but inhibited MMP9, which is responsible for degrading the extracellular matrix, suggesting a significant role of IL1RAP in cell proliferation, migration, and invasion. miR‐19a‐3p, PSG10P, and IL1RAP were all found to be involved in PE pathogenesis. With a common targeting region in their sequences, a regulatory network in the PSG10P/miR‐19a‐3p/IL1RAP pathway may contribute to PE pathogenesis during pregnancy.

The role of epigenetic changes in preeclampsia

“…miR‐19a‐3p expression increased the cell invasion by MMP‐9 expression, enhanced the proliferation by Ki67 expression and decreased apoptosis (indicated by caspase‐3 expression). Expression of miR‐19a‐3p was lower in PE placenta and overexpression of this miRNA could be increased cell invasion and migration under hypoxia . PSG10p is a lncRNA and IL1RAP is a mRNA; IL‐1 can active variety of proteins involved in immunological responses and IL1RAP by IL‐1 regulation in involved in different immune inflammatory response.…”

“…PSG10p is a lncRNA and IL1RAP is a mRNA; IL‐1 can active variety of proteins involved in immunological responses and IL1RAP by IL‐1 regulation in involved in different immune inflammatory response. In addition, IL1RAP can be associated with low active MMP‐9 and more active caspase‐3 and subsequently IL1RAP has critical role in apoptosis . Wang et al showed that IL1RAP and PSG10p expressions are higher in PE placenta compared with normal group and resulted in promotion of trophoblast cells growth and migration.…”

“…In addition, IL1RAP can be associated with low active MMP‐9 and more active caspase‐3 and subsequently IL1RAP has critical role in apoptosis . Wang et al showed that IL1RAP and PSG10p expressions are higher in PE placenta compared with normal group and resulted in promotion of trophoblast cells growth and migration. Moreover, after transfection of miR‐19a‐3p mimics in HTR‐8/SVnevo, the expression of PSG10p was reduced, so these results strongly proved that dysregulation of lncRNA‐PSG10p/miR19a‐3P/IL1RAP networks could be leading to PE disease …”

“…Expression of miR-19a-3p was lower in PE placenta and overexpression of this miRNA could be increased cell invasion and migration under hypoxia. 100 PSG10p is a lncRNA and IL1RAP is a mRNA; IL-1 can active variety of proteins involved in immunological responses 130 and IL1RAP by IL-1 regulation in involved in different immune inflammatory response. In addition, IL1RAP can be associated with low active MMP-9 and more active caspase-3 and subsequently IL1RAP has critical role in apoptosis.…”

“…Moreover, after transfection of miR-19a-3p mimics in HTR-8/SVnevo, the expression of PSG10p was reduced, so these results strongly proved that dysregulation of lncRNA-PSG10p/miR19a-3P/IL1RAP networks could be leading to PE disease. 100 3.3.10 | miRNA-376c and 25-hydroxy vitamin D mRNA expression 25-Hydroxy vitamin D (25-OH-VD) is an essential vitamin of body that can affect the reserve level of vitamin D. 131 The serum 25-OH-VD level in PE is observably decreased compared with normal pregnant women. 131 Moreover, Baker et al 132 described the miRNA-376c expression is low in PE.…”