A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming.
A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming.
复制标题
FoxO3a在滋养层细胞迁移和侵袭中的新作用：从代谢重塑到转录重编程
DOI：
10.1186/s10020-022-00522-4
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发表时间：
2022-08-08
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
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作者：
叉头盒O3a蛋白（FoxO3a）参与了滋养细胞的迁移和侵袭，但其潜在机制尚不清楚。在本研究中，我们旨在探索FoxO3a在胎盘早期发育迁移和侵袭中的转录和代谢调控。用慢病毒载体敲低HTR8/SVneo细胞FoxO3a的表达。Western blot、matrix侵袭实验、伤口愈合实验、海马、基于气相色谱-质谱（GC-MS）的代谢组学、通量组学和RNA-seq转录组学进行了研究。我们发现FoxO3a缺失抑制了HTR8/SVneo细胞的迁移和侵袭。代谢组学、通量组学和海马研究表明，FoxO3a基因敲低导致了有氧呼吸向无氧呼吸的转变，并增加了对细胞外营养物质中芳香氨基酸和长链脂肪酸的利用。此外，我们的RNA-seq也显示FoxO3a敲低后COX-2和MMP9的表达降低，这两个基因与滋养细胞的迁移/侵袭过程密切相关。我们的研究结果提示FoxO3a在胎盘早期发育中的新的生物学作用。FoxO3a通过对COX2、MMP9、芳香氨基酸、能量代谢和氧化应激的调控，对滋养细胞迁移和侵袭发挥重要作用。
The forkhead box O3a protein (FoxO3a) has been reported to be involved in the migration and invasion of trophoblast, but its underlying mechanisms unknown. In this study, we aim to explore the transcriptional and metabolic regulations of FoxO3a on the migration and invasion of early placental development. Lentiviral vectors were used to knock down the expression of FoxO3a of the HTR8/SVneo cells. Western blot, matrigel invasion assay, wound healing assay, seahorse, gas-chromatography-mass spectrometry (GC–MS) based metabolomics, fluxomics, and RNA-seq transcriptomics were performed. We found that FoxO3a depletion restrained the migration and invasion of HTR8/SVneo cells. Metabolomics, fluxomics, and seahorse demonstrated that FoxO3a knockdown resulted in a switch from aerobic to anaerobic respiration and increased utilization of aromatic amino acids and long-chain fatty acids from extracellular nutrients. Furthermore, our RNA-seq also demonstrated that the expression of COX-2 and MMP9 decreased after FoxO3a knockdown, and these two genes were closely associated with the migration/invasion progress of trophoblast cells. Our results suggested novel biological roles of FoxO3a in early placental development. FoxO3a exerts an essential effect on trophoblast migration and invasion owing to the regulations of COX2, MMP9, aromatic amino acids, energy metabolism, and oxidative stress.
影响因子：
4.2
作者：
Zapater JL;Lednovich KR;Layden BT
通讯作者：
Layden BT