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  3. TOP2A deficit-induced abnormal decidualization leads to recurrent implantation failure via the NF-κB signaling pathway

TOP2A deficit-induced abnormal decidualization leads to recurrent implantation failure via the NF-κB signaling pathway

  • Reprod Biol Endocrinol. 2022 Sep 22;20(1):142. doi: 10.1186/s12958-022-01013-1.
Huijia Fu  # 1 2 3,  Wang Tan  # 1 2,  Zhi Chen 4,  Zi Ye 5,  Yuhan Duan 1 2,  Jiayu Huang 1,  Hongbo Qi 6 7 8,  Xiru Liu 9 10
Affiliations

Affiliations

  • 1 Department of Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China.
  • 2 Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, Chongqing Medical University, Chongqing, 400016, China.
  • 3 Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
  • 4 Department of Gynecology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, No, China.
  • 5 Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 6 Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China. qihongbo728@163.com.
  • 7 Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, China. qihongbo728@163.com.
  • 8 Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University (Chongqing Health Center for Women and Children), 400010, Chongqing, China. qihongbo728@163.com.
  • 9 Department of Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China. liuxirupro@163.com.
  • 10 Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China. liuxirupro@163.com.
  • # Contributed equally.
PMID: 36138481 DOI: 10.1186/s12958-022-01013-1
Abstract

Background: Successful implantation is a complex process that is influenced by embryo quality, endometrial receptivity, immune factors, and the specific type of in vitro fertilization protocol used. DNA Topoisomerase IIα (TOP2A) is a well-known protein involved in cell proliferation; however, its expression and effect on the endometrium in recurrent implantation failure (RIF) have not been fully elucidated.

Methods: The human endometrial tissues of healthy controls and patients with RIF were collected. A proteomic analysis was performed to evaluate the differentially expressed proteins between the RIF group and the fertile control group. The expression patterns of TOP2A in the human preimplantation endometrium of the patients with RIF were determined by immunohistochemical staining, Western blotting and qRT-PCR. TOP2A knockdown (sh-TOP2A) T-HESCs were generated using lentiviruses. The expression of TOP2A in T-HESCs was manipulated to investigate its role in decidualization. The TOP2A-related changes in decidualization were screened by mRNA Sequencing in decidualized TOP2A knockdown and control T-HESCs and then confirmed by Western blotting and immunofluorescence staining. TOP2A-deficient mice were generated by injection of TOP2A-interfering adenovirus on GD2.5 and GD3.5.

Results: We performed a proteomic analysis of endometrial tissues to investigate the potential pathogenesis of RIF by comparing the patients with RIF and the matched controls and found that TOP2A might be a key protein in RIF. TOP2A is ubiquitously expressed in both stromal and glandular epithelial cells of the endometrium. The data indicate that TOP2A expression is significantly lower in the mid-secretory endometrium of women with RIF. TOP2A expression was downregulated under stimulation by 8-bromo-cAMP and MPA. Ablation of TOP2A resulted in upregulated expression of decidual biomarkers and morphological changes in the cells. Mechanistic analysis revealed that TOP2A regulates the NF-κB signaling pathway in decidualized T-HESCs. The TOP2A-deficient mice exhibited lower fetal weights.

Conclusions: Our findings revealed that abnormal expression of TOP2A affects decidualization and changes the "window of implantation", leading to RIF. TOP2A participates in the processes of decidualization and embryo implantation, functioning at least in part through the NF-κB pathway. Regulating the expression of TOP2A in the endometrium may become a new strategy for the prevention and treatment of RIF.

Keywords

DNA topoisomerase IIα; Decidualization; Endometrial receptivity; NF-κB; Recurrent implantation failure.

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