Let-7a inhibits Bcl-xl and YAP1 expression to induce apoptosis of trophoblast cells in early-onset severe preeclampsia

• Published in: The Science of the total environment 2020-11, Vol.745, p.139919-139919, Article 139919
• Main Authors: Zha, Wenhui, Guan, Shuang, Liu, Ning, Li, Yang, Tian, Yuan, Chen, Yang, Wang, Yan, Wu, Fuju
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; bcl-X Protein; Bcl-xl; C-caspase-3; C-caspase-9; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Female; Humans; Hypomethylation; Let-7a-3; Mice; Mice, Nude; MicroRNA; MicroRNAs - genetics; Pre-Eclampsia; Preeclampsia; Pregnancy; Trophoblast cells; Trophoblasts; YAP-Signaling Proteins; YAP1
• ISSN: 0048-9697; 1879-1026
• DOI: 10.1016/j.scitotenv.2020.139919

Dysregulation of the MicroRNA (miR) Let-7 family has been implicated in preeclampsia (PE). Abnormal trophoblast cell proliferation and apoptosis associate with the pathogenesis of PE. The present study was designed to test the hypothesis whether let-7a could regulate the biological functions of trophoblasts and explore the mechanism how it works in the development of early-onset severe PE. The putative target genes Bcl-xl and YAP1 of let-7a were verified by luciferase assay. The roles of let-7a, Bcl-xl and YAP1 in regulating JEG-3 cell functions were examined by altering their expression with mimic, overexpression plasmids or siRNAs. The methylation status of let-7a-3 in PE was assessed by methylation-specific and bisulfite sequencing PCR assays. JEG-3 cells were treated with DNA methyltransferase inhibitor to analyze whether let-7a-3 demethylation functioned in PE. Tumor growth and cell apoptosis were measured from nude mice inoculated with JEG-3 cells overexpressing let-7a. The results revealed let-7a was highly expressed in early-onset severe PE and let-7a-3 presented a low methylation level. Functionally, let-7a upregulation could inhibit the viability and cell cycle progression but induce the apoptosis of JEG-3 cells. Bcl-xl and YAP1, target genes of let-7a, could rescue cell apoptosis induced by let-7a. The demethylation of let-7a-3 was also observed to elevate the expression of let-7a and enhance JEG-3 cell apoptosis. Let-7a inhibited tumorigenic ability of JEG-3 cells and enhanced cell apoptosis in vivo. Altogether, let-7a could enhance cell apoptosis in trophoblasts through downregulation of Bcl-xl and YAP1, which suggests that let-7a might be a key regulator in the progression of PE. A schematic map showing the regulation of let-7a in trophoblast apoptosis in early-onset severe preeclampsia by targeting Bcl-xl and YAP1. In early-onset severe preeclampsia, let-7a expression was upregulated by hypomethylation, which subsequently inhibited the expression of Bcl-xl and YAP1 and promoted the expression of Bax, C-Caspase-3 and C-Caspase 9, ultimately resulting in accelerated trophoblast apoptosis and PE progression. [Display omitted] •Let-7a-3 is hypomethylated while let-7a is upregulated in samples of early-onset PE.•Let-7a overexpression promotes apoptosis of trophoblast cells.•Let-7a targets Bcl-xl and YAP1.•Let-7a demethylation induces apoptosis and inhibits tumorigenesis of JEG-3 cells.•This study offers a new target let-7a for the treatment of ea