Abstract
BackgroundInsufficient migration and invasion during trophoblast epithelial-mesenchymal transition (EMT) results in the occurrence and development of preeclampsia (PE), and our previous study has screened 52 miRNAs, whose expression levels are altered in the placental samples from PE patients, compared with the normal group. Among those, miR-3935 is one of the miRNAs being most significantly down-regulated, indicating its involvement in PE. However, the exact effect and molecular mechanisms remain unknown.MethodsIn the present study, we investigate the roles and underlying mechanisms of miR-3935 in trophoblast EMT by use of the human extra-villous trophoblast cell line HTR-8/SVneo as well as human placental tissues and maternal blood samples obtained from 15 women with normal pregnancies and 15 women with PE. Experimental methods include transfection, quantitative reverse transcription-PCR (qRT-PCR), western blot, immunofluorescence staining, dual-luciferase assays, in vitro invasion and migration assays, RNA-Seq analysis, bisulfite sequencing and immunohistochemistry staining.ResultsMiR-3935 expression is significantly decreased in both placentas and peripheral blood specimens of PE, and functionally, miR-3935 promotes EMT of trophoblast cells. Mechanistically, TRAF6 is identified to be a direct target of miR-3935 and TRAF6 exerts its negative effect on EMT of trophoblast cells by inhibition of RGS2, which down-regulates the methylation status of promoter of CDH1 gene that encodes E-Cadherin protein through induction of ALKBH1, resulting in increase of E-Cadherin and subsequently insufficient trophoblast EMT.ConclusionsTogether these results uncover a hitherto uncharacterized role of miR-3935/TRAF6/RGS2 axis in the function of human trophoblasts, which may pinpoint the molecular pathogenesis of PE and may be a prognostic biomarker and therapeutic target for such obstetrical diseases as PE.
Highlights
Preeclampsia (PE), a relatively common pregnancy disorder, is still one of the leading causes of maternal and neonatal morbidity and mortality worldwide, and in the worst cases, may threaten the survival of both motherJin et al Reprod Biol Endocrinol (2021) 19:134 and baby [1,2,3]
TNF receptor associated factor 6 (TRAF6) is identified to be a direct target of miR-3935 and TRAF6 exerts its negative effect on epithelial-mesenchymal transition (EMT) of trophoblast cells by suppression of RGS2, which promotes the methylation status of promoter of CDH1 gene that encodes E-Cadherin protein through down-regulation of the expression of the DNA demethylase ALKBH1, resulting in inhibition of E-Cadherin and subsequently initiation of EMT progression
MiR‐3935 is down‐regulated in preeclamptic placenta To determine the potential involvement of miRNAs in the pathogenesis of preeclampsia (PE), we previously performed a miRNA microarray on placental samples from three PE patients and three women with normal pregnancies [16]
Summary
Preeclampsia (PE), a relatively common pregnancy disorder, is still one of the leading causes of maternal and neonatal morbidity and mortality worldwide, and in the worst cases, may threaten the survival of both motherJin et al Reprod Biol Endocrinol (2021) 19:134 and baby [1,2,3]. At present, increasing evidence has been found in support of the theory of trophoblast superficial implantation, whereby abnormal migration and invasion during trophoblastic epithelial mesenchymal transition (EMT) brings about the occurrence and development of PE [5,6,7]. The invasion of the endometrium on maternal uterine wall and the subsequent proper anchoring of the placenta by trophoblast cells involve a series of changes in trophoblast cell morphology that are completed by placental trophoblast cell EMT, whereas shallow placental implantation and defective spiral artery conversion due to impaired invasion are implicated in the etiology of major placental pathologies, such as PE [6, 7]. Insufficient migration and invasion during trophoblast epithelial-mesenchymal transition (EMT) results in the occurrence and development of preeclampsia (PE), and our previous study has screened 52 miRNAs, whose expression levels are altered in the placental samples from PE patients, compared with the normal group.
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