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A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming

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posted on 20.09.2022, 09:29 authored by Hao Chen, Shi-Han Wang, Chang Chen, Xin-Yang Yu, Jia-Nan Zhu, Toby Mansell, Boris Novakovic, Richard Saffery, Philip N Baker, Ting-Li Han, Hua Zhang
Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Funding

The National Natural Science Foundation of China (No. 81971406, 81771607, 81871185, 81901507, 81961128004), The 111 Project (Yuwaizhuan (2016)32), Chongqing Health Commission (2018ZDXM024), Chongqing Health Commission and Chongqing Science & Technology Commission (2021MSXM121, 2020MSXM101, KJZD-K202100407)

History

Author affiliation

College of Medicine, Biological Sciences and Psychology, University of Leicester

Version

VoR (Version of Record)

Published in

MOLECULAR MEDICINE

Volume

28

Publisher

Springer

issn

1076-1551

eissn

1528-3658

Copyright date

2022

Available date

20/09/2022

Spatial coverage

England

Language

English