br Introduction Maintaining the normal function
Introduction Maintaining the normal function of fetal trophoblasts is essential for a successful pregnancy. Preeclampsia (PE), a pregnancy-specific disorder, is often associated with excessive trophoblast cell apoptosis and superficial trophoblast invasion leading to insufficient spiral artery remodeling and placental hypoxia [, , ]. PE is characterized by new onset hypertension and proteinuria affecting 5–8% of all pregnancies worldwide and representing a leading cause of maternal and perinatal morbidity and mortality [4,5]. Multiple factors have been suggested for the development and progression of PE, however, the precise molecular pathogenesis of PE remains largely unknown . Understanding the genetic and epigenetic alterations involved in trophoblast cell behaviors would help in the development of novel therapeutic targets for the treatment of PE. MicroRNAs (miRNAs) are a class of conserved and non-coding RNAs that regulate gene expression by post-transcriptional repression . The mature miRNAs consisting of 21–25 nucleotides can bind to the 3’-untranslated region (3’-UTR) of target mRNAs in a base-pairing manner, leading to mRNA instability, degradation, and translational repression . Through targeting and regulating target genes, miRNAs can regulate various cellular processes involved in the normal development and onset of diseases . Accumulating evidence has suggested that numerous miRNAs are differentially expressed in human placentas from PE patients [10,11], indicating their potential role in the pathogenesis of PE. Recent studies have reported that miRNAs are involved in regulation of the proliferation, apoptosis, migration, and invasion of trophoblast p2x7 [, , , ]. Therefore, a better understanding the role of miRNA in regulating trophoblast cell behaviors may shed light on development of novel biomarkers for PE diagnosis as well as targets for treatment. Ephrin receptor B4 (EPHB4) is a member of the receptor tyrosine kinase superfamily  and is expressed in endothelial cells of the venous lineage and plays an important role in various diseases [, , ]. Increasing studies have reported that EPHB4 plays a critical role during placentation [, , ]. EPHB4 has been found to regulate the proliferation, apoptosis, migration, and invasion of trophoblast cells involved in the pathogenesis of PE [23,24]. Therefore, EPHB4 may have the potential to be used as a therapeutic target for PE. miR-454 has been reported as an important regulator in various diseases [, , ]. However, whether miR-454 participates in the pathogenesis of PE and regulates trophoblast cell behaviors remains unknown. In this study, we aimed to investigate the potential role of miR-454 in PE. Our results demonstrated that miR-454 expression was significantly downregulated in placental tissues from PE patients. in vitro experiments showed that miR-454 regulated the proliferation, apoptosis, and invasion of trophoblast cells. Interestingly, EPHB4 was identified as a potential target gene of miR-454. Further data revealed that miR-454 negatively regulated EPHB4 expression in trophoblast cells. Moreover, miR-454 expression was inversely correlated with EPHB4 expression in placental tissues from PE patients. Notably, overexpression of EPHB4 partially reversed the promotion effect of miR-454 overexpression on trophoblast cell proliferation and invasion. Taken together, our results demonstrate the miR-454/EPHB4 axis may play an important role in the pathogenesis of PE through regulating trophoblast cell proliferation and invasion.
Materials and methods
Discussion Despite several miRNAs having been reported to participate in the pathogenesis of PE, the precise role of miRNAs in PE remains largely unknown. In this study, we reveal that miR-454 is a novel PE-related miRNA that regulates the proliferation and invasion of trophoblast cells. The underlying mechanism involves the regulatory effect of miR-454 on EPHB4 expression (Fig. 7). Our study suggests that the increased EPHB4 expression induced by miR-454 downregulation may represent an important event in the development and progression of PE.