Dong Li, Wu Haicui, Qi Fanghua, Chen Wen, Xu Yuan, Li Min, Wang Yuqi, Yan Rugen, Cai Pingping
The First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
Department of Reproduction and Genetics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China.
J Ovarian Res. 2025 May 16;18(1):102. doi: 10.1186/s13048-025-01683-6.
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.
长链非编码RNA（lncRNAs）通过多种机制影响颗粒细胞（GCs）的生物学功能，包括表观遗传调控、转录调控、翻译后修饰和细胞信号传导。我们之前的研究发现，lncRNA NEAT1在卵巢储备功能减退（DOR）患者的颗粒细胞中表达显著下调；然而，其确切的调控机制仍不清楚。本研究旨在探讨NEAT1在颗粒细胞功能和DOR发病机制中的作用。我们确定，DOR患者颗粒细胞中NEAT1表达下调与卵巢储备功能和辅助生殖结局密切相关。功能试验表明，NEAT1通过增加S期细胞比例和抑制凋亡来促进KGN细胞增殖。生物信息学分析结合双荧光素酶报告基因试验证实，NEAT1作为miR-204-5p的分子海绵，从而上调miR-204-5p的直接靶基因ESR1。此外，NEAT1和ESR1均表现出显著差异。机制实验表明，NEAT1作为竞争性内源性RNA，通过分子海绵吸附miR-204-5p，从而促进ESR1的表达，并上调参与甾体激素合成的关键酶（类固醇生成急性调节蛋白和细胞色素P450家族19亚家族A成员1）的表达。这诱导雌二醇生物合成并激活下游丝裂原活化蛋白激酶（MAPK）信号通路，增加细胞外信号调节激酶和环磷酸腺苷反应元件结合蛋白的磷酸化，共同驱动细胞周期进程，增强增殖，并抑制KGN细胞凋亡。这表明NEAT1通过miR-204-5p/ESR1/MAPK轴调节颗粒细胞增殖、凋亡和类固醇生成，为DOR发病机制的表观遗传机制提供了新的见解。
