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<p>Long non-coding RNAs (lncRNAs) affect the biological functions of granulosa cells (GCs) through multiple mechanisms, including epigenetic regulation, transcriptional regulation, post-translational modification, and cell signaling. Our previous study found that lncRNA NEAT1 expression is significantly downregulated in the GCs of patients with diminished ovarian reserve (DOR); however, its exact regulatory mechanism remains unclear. This study aimed to investigate the role of NEAT1 in GC function and DOR pathogenesis. We determined that the downregulated NEAT1 expression in the GCs of patients with DOR is closely associated with ovarian reserve function and assisted reproductive outcomes. Functional assays revealed that NEAT1 promotes KGN cell proliferation by increasing the proportion of S-phase cells and inhibiting apoptosis. Bioinformatics analysis combined with dual-luciferase reporter assays confirmed that NEAT1 acts as a molecular sponge for miR-204-5p, thereby upregulating ESR1, a direct target gene of miR-204-5p. Additionally, both NEAT1 and ESR1 exhibited significantly different. Mechanistic experiments demonstrated that NEAT1 acts as a competitive endogenous RNA and adsorbs miR-204-5p through molecular sponging, thereby promoting the expression of ESR1 and upregulating the expression of key enzymes (steroidogenic acute regulatory protein and cytochrome P450 family 19 subfamily A member 1) involved in the synthesis of steroid hormones. This induces estradiol biosynthesis and activates the downstream mitogen-activated protein kinase (MAPK) signaling pathway, increasing the phosphorylation of extracellular signal-related kinase and cyclic adenosine monophosphate response element-binding protein, which collectively drives cell cycle progression, enhances proliferation, and inhibits apoptosis of KGN cells. This suggests that NEAT1 regulates GC proliferation, apoptosis, and steroidogenesis via the miR-204-5p/ESR1/MAPK axis, providing novel insights into the epigenetic mechanisms underlying DOR pathogenesis.</p>

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LncRNA NEAT1 participates in diminished ovarian reserve by affecting granulosa cell apoptosis and estradiol synthesis via the miR-204-5p/ESR1 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月16日

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  • Li Dong,
  • Haicui Wu,
  • Fanghua Qi,
  • Wen Chen,
  • Yuan Xu,
  • Min Li,
  • Yuqi Wang,
  • Rugen Yan,
  • Pingping Cai

摘要

Long non-coding RNAs (lncRNAs) affect the biological functions of granulosa cells (GCs) through multiple mechanisms, including epigenetic regulation, transcriptional regulation, post-translational modification, and cell signaling. Our previous study found that lncRNA NEAT1 expression is significantly downregulated in the GCs of patients with diminished ovarian reserve (DOR); however, its exact regulatory mechanism remains unclear. This study aimed to investigate the role of NEAT1 in GC function and DOR pathogenesis. We determined that the downregulated NEAT1 expression in the GCs of patients with DOR is closely associated with ovarian reserve function and assisted reproductive outcomes. Functional assays revealed that NEAT1 promotes KGN cell proliferation by increasing the proportion of S-phase cells and inhibiting apoptosis. Bioinformatics analysis combined with dual-luciferase reporter assays confirmed that NEAT1 acts as a molecular sponge for miR-204-5p, thereby upregulating ESR1, a direct target gene of miR-204-5p. Additionally, both NEAT1 and ESR1 exhibited significantly different. Mechanistic experiments demonstrated that NEAT1 acts as a competitive endogenous RNA and adsorbs miR-204-5p through molecular sponging, thereby promoting the expression of ESR1 and upregulating the expression of key enzymes (steroidogenic acute regulatory protein and cytochrome P450 family 19 subfamily A member 1) involved in the synthesis of steroid hormones. This induces estradiol biosynthesis and activates the downstream mitogen-activated protein kinase (MAPK) signaling pathway, increasing the phosphorylation of extracellular signal-related kinase and cyclic adenosine monophosphate response element-binding protein, which collectively drives cell cycle progression, enhances proliferation, and inhibits apoptosis of KGN cells. This suggests that NEAT1 regulates GC proliferation, apoptosis, and steroidogenesis via the miR-204-5p/ESR1/MAPK axis, providing novel insights into the epigenetic mechanisms underlying DOR pathogenesis.