Abstract
Preeclampsia is a common, pregnancy-specific disease and a major contributor to maternal and foetal morbidity and mortality. Some placental abnormalities, including deficient implantation, abnormal trophoblast cell function, and improper placental vascular development, are believed to lead to preeclampsia. The long noncoding RNA SPRY4-IT1 is more highly expressed in preeclamptic human placentas than in normal placentas. We assessed the role of epithelial-mesenchymal transition (EMT)-associated invasion and migration in HTR-8/SVneo trophoblast cells. Overexpression of SPRY4-IT1 suppressed trophoblast cell migration and invasion, whereas reduced expression of SPRY4-IT1 prevented the EMT process. Mechanistically, an RNA immunoprecipitation experiment showed that SPRY4-IT1 bound directly to HuR and mediated the β-catenin expression associated with EMT in HTR-8/SVneo cells. Moreover, the expression levels of genes in the WNT family, such as WNT3 and WNT5B, were changed after transfection of HTR-8/SVneo with SPRY4-IT1. Together, our results highlight the roles of SPRY4-IT1 in causing trophoblast cell dysfunction by acting through the Wnt/β-catenin pathway, and consequently in impairing spiral artery remodelling. These results suggest a new potential therapeutic target for intervention against preeclampsia.
Highlights
Among these characteristics, poor spiral artery remodelling has been considered to be a crucial early defect that causes PE and foetal growth restriction[6]
We found that SPRY4-IT1 inhibits trophoblast cell migration and invasion partly via regulating the epithelial-mesenchymal transition (EMT) process and may affect Wnt/β-catenin signalling
We evaluated mRNA levels of members of the WNT family that have been reported to be associated with the EMT process, including WNT1, WNT2, WNT3, and WNT5b
Summary
Poor spiral artery remodelling has been considered to be a crucial early defect that causes PE and foetal growth restriction[6]. The acquisition of migratory and invasive phenotypes by trophoblasts is an important aspect of the epithelial-to-mesenchymal transition (EMT)[11]. Lan Xiao et al have shown that SPRY4-I1 is required for HuR binding to RNA; it directly interacts with tight junction mRNAs and regulates intestinal epithelial barrier function[23] in human placental tissues, SPRY4-IT1 exhibits differential expression in severe PE placenta, and it contributes to the biological activities of trophoblasts[24]. On the basis of these findings and according to the crucial influence of trophoblast migration and invasion, we further investigated the potential molecular mechanism by which SPRY4-IT1 regulates spiral artery remodelling in PE. We found that SPRY4-IT1 inhibits trophoblast cell migration and invasion partly via regulating the EMT process and may affect Wnt/β-catenin signalling
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