MicroRNA‐210 regulates human trophoblast cell line HTR‐8/SVneo function by attenuating Notch1 expression: Implications for the role of microRNA‐210 in pre‐eclampsia

Abstract

Successful pregnancy depends on the precise regulation of extravillous trophoblast cell invasion ability. MicroRNA‐210‐3p (miR‐210), which is increased in the placenta of pre‐eclampsia. Furthermore, miR‐210 could inhibit trophoblasts invasion and might act as a serum biomarker for pre‐eclampsia. Previous studies have demonstrated that miR‐210 regulates HUVEC (human umbilical vein endothelial cell)‐mediated angiogenesis by regulating the NOTCH1 signaling pathway. Studies by our group have previously identified that NOTCH1 plays a positive role in regulating trophoblast functions. However, the miR‐210/NOTCH1 signaling pathway in the regulation of trophoblasts and pre‐eclampsia has not been characterized. Therefore, this study was conducted to investigate the role of miR‐210 and its relationship with NOTCH1 in trophoblasts. We first examined the expression levels of miR‐210 and NOTCH1 in pre‐eclamptic and normals placentas. Next, the expression and location of miR‐210 and NOTCH1 in the first‐trimester villi, maternal decidua, and placenta of late pregnancy were shown via in situ hybridization and immunohistochemistry. The trophoblast cell line HTR‐8/SVneo was used to investigate the effects of miR‐210 on the expression of NOTCH1 and cell bioactivity by upregulation and downregulation strategies. The results showed that miR‐210 expression was increased, whereas NOTCH1 expression was decreased in pre‐eclamptic placenta compared with controls. Upregulation of miR‐210 decreased NOTCH1 expression, impaired HTR‐8/SVneo proliferation, migration, invasion, and tube‐like formation capabilities, and promoted apoptosis. In contrast, downregulation of miR‐210 resulted in the opposite effects. These findings suggested that miR‐210 might act as a contributor to trophoblast dysfunction by attenuating NOTCH1 expression.

Molecular mechanism of the effect of angiopoietin‑like protein 8 on the proliferation, invasion and migration of placental trophoblasts in preeclampsia

“…It is widely accepted that excessive apoptosis and poor invasion of trophoblast cells serve major roles in the pathogenesis of PE. Wang et al reported that regulation of the microRNA-210/NOTCH1 signaling pathway attenuated the impaired HTR-8/SVneo cell proliferation, migration and invasion, which contributed to trophoblast dysfunction in the placenta of patients with PE (27). This is consistent with the data of the present study, which indicated that downregulation of ANGPTL8 increased the viability and proliferation of HTR8/SVneo cells (Fig.…”

Recent Advances of MicroRNAs, Long Non-coding RNAs, and Circular RNAs in Preeclampsia

“…In another study, up-regulation of miR-210 reduced Notch1 expression; impaired HTR8/SVneo proliferation, migration, invasion, and tubule formation; and promoted apoptosis; down-regulation of miR-210 had the opposite effects. These findings suggest that miR-210 plays a role in trophoblast dysfunction by reducing Notch1 expression (Wang R. et al, 2019).…”

“…In general, Each miRNA has multiple target genes, such as miR-210, which not only targets HSD17B1s (Song et al, 2015), but also targets PTPN2 , KCMF1 (Luo et al, 2014), THSD7A (Tian et al, 2020), and Notch1 (Wang R. et al, 2019) to regulate the biological function of trophoblast and participate in vascular remodeling, growth and tube formation. Besides, several miRNAs also target the same gene.…”

Roles of noncoding RNAs in preeclampsia

“…In view of the role of miR-210 in PE, related studies with larger sample sizes further confirmed that the placental expression of miR-210 in patients with PE did indeed increase significantly compared to the corresponding levels experienced during normal pregnancy [ 18 – 20 ]. miR-210 can inhibit the proliferation, invasion, and angiogenesis of trophoblasts by acting on the downstream target genes that encode KCMF1 [ 20 ], NOTCH1 [ 21 ] and MAPK [ 18 ]. Upregulated levels of miR-210 have also been detected in peripheral blood serum [ 18 ].…”