Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, China.
J Cell Mol Med. 2019 Feb;23(2):852-864. doi: 10.1111/jcmm.13985. Epub 2018 Oct 28.
Preeclampsia (PE), a pregnancy-specific disorder, is a leading cause of perinatal maternal-fetal mortality and morbidity. Impaired cell migration and invasion of trophoblastic cells and an imbalanced systemic maternal inflammatory response have been proposed as potential mechanisms of PE pathogenesis. Comparative analysis between PE placentas and normal placentas profiled differentially expressed miRNAs, lncRNAs, and mRNAs, including miR-19a-3p (miRNA), PSG10P (lncRNA), and IL1RAP (mRNA). This study was conducted to investigate their potential roles in PE pathogenesis. The expression of miR-19a-3p, PSG10P, and IL1RAP was examined in PE and normal placentas using RT-qPCR. An in vitro experiment was performed in human trophoblast HET8/SVneo and TEV-1 cells cultured in normoxic and hypoxic conditions. MiR-19a-3p targets were identified using Targetscan, miRanda, and PicTar analysis as well as luciferase reporter assays. The mouse model of PE was conducted using sFlt-1 for in vivo tests. Lower levels of miR-19a-3p, but higher levels of PSG10P and IL1RAP were observed in PE placentas and the trophoblast cells in hypoxia. Luciferase reporter assays confirmed that PSG10P and IL1RAP were both direct targets of miR-19a-3p. Exposure to hypoxia inhibited cell viability, migration, and invasion of HET8/SVneo and TEV-1 cells. Knocking out PSG10P and IL1RAP or overexpressing miR-19a-3p rescued the inhibition caused by hypoxia. In vivo experiments showed that IL1RAP promoted the expression of caspase-3, a key apoptosis enzyme, but inhibited MMP9, which is responsible for degrading the extracellular matrix, suggesting a significant role of IL1RAP in cell proliferation, migration, and invasion. miR-19a-3p, PSG10P, and IL1RAP were all found to be involved in PE pathogenesis. With a common targeting region in their sequences, a regulatory network in the PSG10P/miR-19a-3p/IL1RAP pathway may contribute to PE pathogenesis during pregnancy.
子痫前期（PE）是一种妊娠特有的疾病，是围产期母婴死亡率和发病率的主要原因。滋养细胞的细胞迁移和侵袭受损以及系统性母体炎症反应失衡被认为是 PE 发病机制的潜在机制。PE 胎盘与正常胎盘之间的比较分析描绘了差异表达的 miRNA、lncRNA 和 mRNA，包括 miR-19a-3p（miRNA）、PSG10P（lncRNA）和 IL1RAP（mRNA）。本研究旨在探讨它们在 PE 发病机制中的潜在作用。使用 RT-qPCR 检测 miR-19a-3p、PSG10P 和 IL1RAP 在 PE 和正常胎盘中的表达。在常氧和缺氧条件下培养的人滋养细胞 HET8/SVneo 和 TEV-1 细胞中进行体外实验。使用 Targetscan、miRanda 和 PicTar 分析以及荧光素酶报告基因测定鉴定 miR-19a-3p 的靶标。使用 sFlt-1 进行 PE 的小鼠模型进行体内试验。PE 胎盘和缺氧滋养细胞中观察到 miR-19a-3p 水平降低，而 PSG10P 和 IL1RAP 水平升高。荧光素酶报告基因测定证实 PSG10P 和 IL1RAP 都是 miR-19a-3p 的直接靶标。缺氧暴露抑制 HET8/SVneo 和 TEV-1 细胞的活力、迁移和侵袭。敲除 PSG10P 和 IL1RAP 或过表达 miR-19a-3p 可挽救缺氧引起的抑制。体内实验表明，IL1RAP 促进关键凋亡酶 caspase-3 的表达，但抑制负责降解细胞外基质的 MMP9，表明 IL1RAP 在细胞增殖、迁移和侵袭中起重要作用。miR-19a-3p、PSG10P 和 IL1RAP 均参与 PE 的发病机制。由于它们序列中有一个共同的靶向区域，因此 PSG10P/miR-19a-3p/IL1RAP 通路中的调控网络可能有助于妊娠期间 PE 的发病机制。
