Liu Ting, Li Wei, Zhang Jing, Zhang Yan
Department of Obstetrics, Zibo Maternal and Child Health Hospital, Zibo, 255022, Shandong Province, China.
Department of Gynecology, Hainan General Hospital, Haikou, 570311, Hainan Province, China.
Reprod Sci. 2022 May;29(5):1486-1497. doi: 10.1007/s43032-021-00793-y. Epub 2021 Nov 18.
MiR-222-3p was found to be upregulated in plasma of patients with severe preeclampsia (PE). However, its role in PE progression remains elusive. This study aimed to explore the underlying role and mechanism of miR-222-3p in PE progression. Herein, we verified that miR-222-3p was upregulated and HDAC6 mRNA was downregulated in placentas of PE patients compared with normal pregnant controls as measured by RT-qPCR. And miR-222-3p expression was negatively correlated with HDAC6 mRNA expression in PE patients. HTR8/SVneo trophoblast cells were transfected with miR-222-3p mimic or miR-222-3p inhibitor, and we found that MiR-222-3p overexpression inhibited proliferation, migration, and matrix metalloproteinase (MMP)-2 and MMP-9 levels in HTR-8/SVneo cells, while miR-222-3p silencing showed the opposite results. Online bioinformatics analysis and dual-luciferase reporter assay confirmed that HDAC6 was a target of miR-222-3p. HDAC6 overexpression promoted HTR-8/SVneo cell proliferation and migration, while HDAC6 knockdown suppressed cell proliferation and migration. Moreover, HDAC6 overexpression and Notch1 signaling activation both reversed the inhibitory effects of miR-222-3p on trophoblast cell proliferation and migration. Additionally, treatment with miR-222-3p inhibitor attenuated blood pressure and fetal detrimental changes in PE rats. Collectively, our findings suggested that MiR-222-3p inhibited HDAC6 expression and blocked the Notch1 signaling, thus suppressing trophoblast cell proliferation and migration and attenuating blood pressure and fetal detrimental changes in PE rats, which is expected to become a therapeutic target for PE.
研究发现，重度子痫前期（PE）患者血浆中的miR-222-3p上调。然而，其在PE进展中的作用仍不清楚。本研究旨在探讨miR-222-3p在PE进展中的潜在作用及机制。在此，我们通过RT-qPCR检测证实，与正常妊娠对照组相比，PE患者胎盘组织中miR-222-3p上调，HDAC6 mRNA下调。并且，PE患者中miR-222-3p表达与HDAC6 mRNA表达呈负相关。用miR-222-3p模拟物或miR-222-3p抑制剂转染HTR8/SVneo滋养层细胞，我们发现miR-222-3p过表达抑制HTR-8/SVneo细胞的增殖、迁移以及基质金属蛋白酶（MMP）-2和MMP-9水平，而miR-222-3p沉默则产生相反的结果。在线生物信息学分析和双荧光素酶报告基因检测证实HDAC6是miR-222-3p的靶标。HDAC6过表达促进HTR-8/SVneo细胞增殖和迁移，而HDAC6基因敲低则抑制细胞增殖和迁移。此外，HDAC6过表达和Notch1信号激活均逆转了miR-222-3p对滋养层细胞增殖和迁移的抑制作用。另外，用miR-222-3p抑制剂处理可减轻PE大鼠的血压和胎儿有害变化。总的来说，我们的研究结果表明，miR-222-3p抑制HDAC6表达并阻断Notch1信号，从而抑制滋养层细胞增殖和迁移，并减轻PE大鼠的血压和胎儿有害变化，有望成为PE的治疗靶点。
