Department of Obstetrics, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, No. 2, Jingba Road, Zhengzhou, Henan, People's Republic of China.
Hum Cell. 2024 Sep;37(5):1405-1420. doi: 10.1007/s13577-024-01095-6. Epub 2024 Jul 15.
Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE.
滋养细胞功能异常与子痫前期（PE）的发病机制有关。核受体亚家族 2 组 F 成员 1（NR2F1）在许多疾病中作为转录调节剂发挥作用，但它在 PE 中的作用尚不清楚。缺氧/复氧（H/R）刺激 HTR-8/SVneo 细胞用于体外模拟 PE 损伤。NR2F1 过表达减轻滋养细胞凋亡，这表现在 TUNEL 阳性细胞数量减少和细胞中 caspase 3 和 caspase 9 表达下调。NR2F1 过表达增加 HTR-8/SVneo 细胞的侵袭和迁移能力，伴随着基质金属蛋白酶（MMP）-2 和 MMP-9 蛋白水平的增加。mRNA-seq 用于探索 NR2F1 的潜在机制，确定生长分化因子 15（GDF15）为可能的下游效应物。双荧光素酶报告基因、ChIP-qPCR 和 DNA 下拉实验证实 NR2F1 与 GDF15 启动子结合并转录抑制其表达。GDF15 过表达增加了表达 NR2F1 的 HTR-8/SVneo 细胞的凋亡，降低了侵袭和迁移能力。MAPK 途径参与了 PE 的调节。p38 抑制剂、ERK 抑制剂和 JNK 抑制剂的给药逆转了同时过表达 NR2F1 和 GDF15 对滋养细胞凋亡、侵袭和迁移的影响。我们的研究结果表明，NR2F1 过表达抑制滋养细胞凋亡并促进滋养细胞侵袭和迁移。NR2F1 可能通过结合其启动子区域负调控 GDF15 的表达，从而进一步抑制 PE 中的 MAPK 信号通路。我们的研究强调，NR2F1 可能作为 PE 的潜在靶点。
