Department of Obstetrics and Gynecology, Tangshan Worker Hospital, Hebei Medical University, Tangshan, Hebei 063000, P.R. China.
Department of Rheumatology and Immunology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, P.R. China.
Mol Med Rep. 2019 May;19(5):3775-3782. doi: 10.3892/mmr.2019.9997. Epub 2019 Mar 1.
Insufficient invasion of trophoblasts is known to be associated with preeclampsia (PE) development. Recently, microRNAs (miRNAs) have been reported to serve important roles in the pathogenesis of PE. However, little is known regarding the regulation of trophoblastic invasion by miRNAs. The aim of the present study was to explore the role of miRNAs in trophoblastic invasion and the underlying molecular mechanism. Using a miRNA microarray, miRNAs putatively involved in the pathophysiology of PE were examined between normal and preeclamptic placentas. Validation analysis of miR‑142‑3p level in placenta specimens was performed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Then, the regulation of miR‑142‑3p on trophoblast cells migration and invasion was evaluated using wound healing and transwell migration assays. Furthermore, the target gene of miR‑142‑3p and the downstream signaling pathway were also investigated. Microarray analysis and RT‑qPCR revealed that miR‑142‑3p was significantly upregulated in placenta specimens from patients with PE. Its overexpression inhibited trophoblast cell invasion and migration, whereas its knockdown enhanced trophoblast cell invasion and migration. In addition, overexpression of miR‑142‑3p inhibited the mRNA expression and the activities of matrix metalloproteinase‑2 (MMP2) and MMP9, which are closely associated with cell invasion and migration, while inhibition of miR‑142‑3p had the opposite result. Subsequent analyses demonstrated that transforming growth factor‑β1 (TGF‑β1) was a direct and functional target of miR‑142‑3p. Notably, the knockdown of TGF‑β1 effectively reversed the enhancement of miR‑142‑3p inhibitor on trophoblast cell invasion and migration. Finally, the present study confirmed that miR‑142‑3p inhibitor enhanced cell invasion and migration by reactivating the TGF‑β1/Smad3 signaling pathway. Taken together, the results of the present study suggest that miR‑142‑3p may serve an important role in human placental development by suppressing trophoblast cell invasion and migration through disruption of the TGF‑β1/smad3 signaling pathway, suggesting that knockdown of miR‑142‑3p may provide a novel therapy for PE.
滋养细胞侵袭不足已知与子痫前期 (PE) 的发展有关。最近，microRNAs (miRNAs) 已被报道在 PE 的发病机制中发挥重要作用。然而，关于 miRNA 对滋养细胞侵袭的调节知之甚少。本研究旨在探讨 miRNA 在滋养细胞侵袭中的作用及其潜在的分子机制。
使用 miRNA 微阵列，在正常和子痫前期胎盘之间检测与 PE 病理生理学相关的 miRNA。使用逆转录-定量聚合酶链反应 (RT-qPCR) 对胎盘标本中 miR-142-3p 水平进行验证分析。然后，使用划痕愈合和 Transwell 迁移实验评估 miR-142-3p 对滋养细胞迁移和侵袭的调节作用。此外，还研究了 miR-142-3p 的靶基因和下游信号通路。
微阵列分析和 RT-qPCR 显示，PE 患者胎盘标本中 miR-142-3p 表达显著上调。其过表达抑制滋养细胞侵袭和迁移，而敲低则增强滋养细胞侵袭和迁移。此外，miR-142-3p 的过表达抑制与细胞侵袭和迁移密切相关的基质金属蛋白酶-2 (MMP2) 和 MMP9 的 mRNA 表达和活性，而 miR-142-3p 的抑制则产生相反的结果。随后的分析表明，转化生长因子-β1 (TGF-β1) 是 miR-142-3p 的直接和功能靶标。值得注意的是，TGF-β1 的敲低有效逆转了 miR-142-3p 抑制剂对滋养细胞侵袭和迁移的增强作用。
最后，本研究证实 miR-142-3p 抑制剂通过重新激活 TGF-β1/Smad3 信号通路增强细胞侵袭和迁移。综上所述，本研究表明 miR-142-3p 通过破坏 TGF-β1/smad3 信号通路抑制滋养细胞侵袭和迁移，在人胎盘发育中可能发挥重要作用，提示敲低 miR-142-3p 可能为 PE 提供一种新的治疗方法。
