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微小 RNA-491-5p 通过靶向基质金属蛋白酶-9 抑制子痫前期滋养细胞迁移和侵袭。

MicroRNA‑491‑5p inhibits trophoblast cell migration and invasion through targeting matrix metalloproteinase‑9 in preeclampsia.

机构信息

Department of Obstetrics and Gynecology, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei 063000, P.R. China.

Department of Immunity, Tangshan Gongren Hospital, Hebei Medical University, Tangshan, Hebei 063000, P.R. China.

出版信息

Mol Med Rep. 2020 Dec;22(6):5033-5040. doi: 10.3892/mmr.2020.11604. Epub 2020 Oct 14.

Abstract

Insufficient invasion of trophoblasts is correlated with the development of preeclampsia (PE). MicroRNA (miR)‑491‑5p has been reported to be implicated in human cancer cell invasion; however, whether miR‑491‑5p is involved in the development of PE remains largely unclear. The aim of the present study was to investigate the role of miR‑491‑5p in trophoblastic invasion in vitro and to determine its underlying mechanism of action. The expression levels of miR‑491‑5p were validated using reverse transcription‑quantitative PCR. The effects of miR‑491‑5p on trophoblast cell invasion were evaluated in vitro. Then, the association between miR‑491‑5p and its downstream target was investigated in both cell lines and clinical specimens. miR‑491‑5p expression levels were observed to be significantly increased in the placental tissues from patients with PE. The invasive capacity of HTR‑8/SVneo trophoblast cells was suppressed following the upregulation of miR‑491‑5p and increased following the inhibition of miR‑491‑5p. Matrix metalloproteinase‑9 (MMP‑9), a well‑known regulator of trophoblast cell invasion, was discovered to be a direct target of miR‑491‑5p in HTR‑8/SVneo trophoblast cells. Moreover, miR‑491‑5p expression levels were found to be inversely correlated with MMP‑9 expression levels in placental tissues from patients with PE. The overexpression of MMP‑9 partly attenuated the inhibitory effects of miR‑491‑5p on HTR‑8/SVneo trophoblast cells invasion. Collectively, these findings suggested that the aberrant expression of miR‑491‑5p may contribute to PE through suppressing trophoblast invasion, thus highlighting the novel roles of miR‑491‑5p in the molecular pathogenesis of PE. The present study also showed that the miR‑491‑5p/MMP‑9 axis may be an effective biomarker or a viable drug target for therapeutic intervention in PE.

摘要

滋养细胞侵袭不足与子痫前期 (PE) 的发展有关。已有研究报道,微小 RNA (miR) -491-5p 参与了人类癌细胞的侵袭;然而,miR-491-5p 是否参与了 PE 的发展尚不清楚。本研究旨在探讨 miR-491-5p 在滋养细胞体外侵袭中的作用及其潜在的作用机制。采用逆转录-定量 PCR 验证 miR-491-5p 的表达水平。体外评估 miR-491-5p 对滋养层细胞侵袭的影响。然后,在细胞系和临床标本中研究了 miR-491-5p 与其下游靶标的相关性。研究发现,PE 患者胎盘组织中 miR-491-5p 的表达水平显著升高。上调 miR-491-5p 后可抑制 HTR-8/SVneo 滋养细胞的侵袭能力,而下调 miR-491-5p 后则可增强其侵袭能力。基质金属蛋白酶-9 (MMP-9) 是滋养细胞侵袭的已知调节因子,在 HTR-8/SVneo 滋养细胞中被发现是 miR-491-5p 的直接靶标。此外,还发现 miR-491-5p 的表达水平与 PE 患者胎盘组织中 MMP-9 的表达水平呈负相关。过表达 MMP-9 部分减弱了 miR-491-5p 对 HTR-8/SVneo 滋养细胞侵袭的抑制作用。综上所述,这些发现表明,miR-491-5p 的异常表达可能通过抑制滋养细胞侵袭导致 PE,从而凸显了 miR-491-5p 在 PE 分子发病机制中的新作用。本研究还表明,miR-491-5p/MMP-9 轴可能是 PE 治疗干预的有效生物标志物或可行的药物靶点。

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