子宫腺肌病中 TCF21 的异常上调会通过增加 PDE4C 的表达而损害子宫内膜的蜕膜化。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-09-25 DOI:10.1016/j.bbadis.2024.167526

Ruoer Yu , Chenxuan Wei , Guojing Li, Jing Ouyang, Na Liu, Nihao Gu, Yu Lin, Hong Xu

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引用次数: 0

摘要

背景：蜕膜化受损是子宫腺肌症（AM）患者不孕的主要原因。然而，转录因子21（TCF21）对AM的影响以及相关蜕膜化受损的潜在机制仍不清楚。本研究的目的是调查TCF21在AM患者子宫内膜组织中的表达，以及其损害人子宫内膜基质细胞（HESCs）蜕膜化的具体机制，以期改善AM不孕患者的生殖结局：方法：我们通过转录组学比较了对照组和AM相关的复发性着床失败（RIF）组的基因表达。此外，我们还通过qRT-PCR、免疫荧光和Western印迹证实了TCF21的高表达会影响蜕膜化。在HESCs中过表达TCF21后，我们进行了RNA-seq分析，以确定体外蜕膜过程中与TCF21相关的分子变化。然后，我们进行了ChIP-seq/qPCR和双荧光素酶报告实验，以探索TCF21与PDE4C之间的确切相互作用。结果显示：RNA-seq分析显示，TCF21与PDE4C之间存在相互作用，并通过IHC、qRT-PCR、Western blot和ELISA等方法进一步证实了相关的下游机制：结果：RNA-seq分析显示，与对照组相比，AM相关RIF组子宫内膜中TCF21的表达明显升高。我们使用 AM 患者和对照组的样本证实了同样的结果。通过抑制蜕膜标志物和细胞骨架的改变，TCF21在HESCs中的过表达损害了蜕膜化。机理分析表明，TCF21通过直接增加PDE4C的表达和抑制FOXO1的表达来抑制细胞内cAMP水平：结论：TCF21通过PDE4C/cAMP-FOXO1轴损害AM患者的蜕膜化，这为蜕膜化相关不孕症的病理学提供了有价值的见解，并指出了改善AM患者子宫内膜接受性的潜在治疗方法。

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Aberrant TCF21 upregulation in adenomyosis impairs endometrial decidualization by increasing PDE4C expression

Background

Impaired decidualization is a major cause of infertility in patients with adenomyosis (AM). However, the effect of transcription factor 21 (TCF21) on AM and the underlying mechanism of associated-impaired decidualization remain unclear. The aim of this study was to investigate the expression of TCF21 in endometrial tissues of AM patients and the specific mechanisms by which it impairs the decidualization of human endometrial stromal cells (HESCs), with a view to improving the reproductive outcome of AM infertile patients.

Methods

We compared gene expressions via transcriptomics between the control and AM-associated recurrent implantation failure (RIF) groups. qRT-PCR, western blot, and IHC were performed to confirm the expression and location of TCF21 in the endometrium. Furthermore, we confirmed that high expression of TCF21 impairs decidualization by qRT-PCR, immunofluorescence, and western blot. RNA-seq following overexpression of TCF21 in HESCs was conducted to identify TCF21-related molecular changes during in vitro decidualization. Then we performed ChIP-seq/qPCR and dual-luciferase reporter assay to explore the exact interaction between TCF21 and PDE4C. The related downstream mechanisms were further proved using IHC, qRT-PCR, western blot, and ELISA.

Results

According to the RNA-seq analysis, TCF21 expression was remarkably higher in the endometrium of the AM-related RIF group compared to the control group. We confirmed the same results using samples from patients with AM and controls. TCF21 overexpression in HESCs impaired decidualization through suppression of decidual markers and cytoskeleton alterations. The mechanistic analysis revealed that TCF21 inhibited intracellular cAMP levels by directly increasing PDE4C expression and suppressing FOXO1 expression.

Conclusions

TCF21 compromises decidualization in patients with AM via the PDE4C/cAMP-FOXO1 axis, which offers valuable insights on the pathology of decidualization-related infertility and indicates a potential treatment to improve endometrial receptivity in AM.

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.