2. Academic Validation
  3. LDHA deficiency inhibits trophoblast proliferation via the PI3K/AKT/FOXO1/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion

LDHA deficiency inhibits trophoblast proliferation via the PI3K/AKT/FOXO1/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion

  • FASEB J. 2023 Feb;37(2):e22744. doi: 10.1096/fj.202201219RR.
Yueyue Zhu 1 2 3,  Fan Wu 1,  Jianing Hu 1 2 3,  Yichi Xu 1 2 3,  Jinwen Zhang 1 2 3,  Yan Li 4,  Yi Lin 1 5,  Xiaorui Liu 1 2 3
Affiliations

Affiliations

  • 1 The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
  • 3 Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Center for Reproductive Medicine, Shandong University, Jinan, China.
  • 5 Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
PMID: 36583693 DOI: 10.1096/fj.202201219RR
Abstract

Dysregulated trophoblast proliferation, invasion, and Apoptosis may cause several pregnancy-associated complications, such as unexplained recurrent spontaneous abortion (URSA). Recent studies have shown that metabolic abnormalities, including glycolysis inhibition, may dysregulate trophoblast function, leading to URSA. However, the underlying mechanisms remain unclear. Herein, we found that Lactate Dehydrogenase A (LDHA), a key Enzyme in glycolysis, was significantly reduced in the placental villus of URSA patients. The human trophoblast cell line HTR-8/SVneo was used to investigate the possible LDHA-mediated regulation of trophoblast function. LDHA knockdown in HTR-8/SVneo cells induced G0/G1 phase arrest and increased Apoptosis, whereas LDHA overexpression reversed these effects. Next, RNA sequencing combined with Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the PI3K/Akt signaling pathway is potentially affected by downstream genes of LDHA. Especially, we found that LDHA knockdown decreased the phosphorylation levels of PI3K, Akt, and FOXO1, resulting in a significant downregulation of CyclinD1. In addition, treatment with an Akt Inhibitor or FOXO1 inhibitor also verified that the PI3K/Akt/FOXO1 signaling pathway influenced the gene expression of CyclinD1 in trophoblast. Moreover, p-AKT expression correlated positively with LDHA expression in syncytiotrophoblasts and extravillous trophoblasts in first-trimester villus. Collectively, this study revealed a new regulatory pathway for LDHA/PI3K/Akt/FOXO1/CyclinD1 in the trophoblast cell cycle and proliferation.

Keywords

CyclinD1; LDHA; cleaved caspase-7; p-AKT.

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