Yan Sisi, Qu Bing, Chen Yu, Wu Qiuji, Ding Jinli, Qiu Hui
Hubei Key Laboratory of Tumor Biological Behaviors, Department of Radiation and Medical Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Front Cell Dev Biol. 2025 May 23;13:1585987. doi: 10.3389/fcell.2025.1585987. eCollection 2025.
Polycystic ovary syndrome (PCOS) is characterized by follicular dysplasia, with granulosa cells (GCs) glycolysis playing a pivotal role in this pathology. Although the involvement of long noncoding RNAs (lncRNAs) in diverse biological processes of PCOS has been well documented, the molecular mechanism of lncRNA small nucleolar RNA host gene 12 (SNHG12) in PCOS remains unclear.
In this study, we measured SNHG12 expression in GCs of PCOS patients and healthy controls using RT-PCR and performed correlation analysis between SNHG12 expression and glycolytic markers. Using granulosa-like tumor (KGN) cells, we investigated glycolytic capacity and examined the relationship among SNHG12, PTEN and HMGB1 through RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays. Finally, DHEA-induced PCOS mice was constructed using SNHG12 adenovirus to explore its role in PCOS.
SNHG12 expression was significantly downregulated in GCs from PCOS patients compared with healthy controls, and showed positive correlation with glycolytic markers. Functional studies demonstrated that SNHG12 knockdown impaired glycolysis in KGN cells, while SNHG12 overexpression partially restored glycolysis. Furthermore, SNHG12-induced glycolysis affected apoptosis of KGN cells, which mediated follicular dysplasia through lactate production and apoptotic pathways. , adenovirus-mediated SNHG12 overexpression alleviated the symptoms of PCOS mice. Mechanistically, RIP and ChIP assays revealed that SNHG12 interacts with HMGB1 and inhibits PTEN transcription by preventing HMGB1 from binding to the PTEN promoter, thereby promoting glycolysis in KGN cells.
Our findings collectively demonstrate that the SNHG12/HMGB1/PTEN axis serves as a novel regulatory mechanism in PCOS by modulating glycolytic-mediated follicular dysplasia in GCs, offering a potential therapeutic target for PCOS.
多囊卵巢综合征（PCOS）的特征是卵泡发育异常，其中颗粒细胞（GCs）糖酵解在该病理过程中起关键作用。尽管长链非编码RNA（lncRNAs）参与PCOS多种生物学过程已有充分记录，但lncRNA小核仁RNA宿主基因12（SNHG12）在PCOS中的分子机制仍不清楚。
在本研究中，我们使用逆转录聚合酶链反应（RT-PCR）检测PCOS患者和健康对照者GCs中SNHG12的表达，并对SNHG12表达与糖酵解标志物进行相关性分析。利用类颗粒细胞瘤（KGN）细胞，我们研究了糖酵解能力，并通过RNA免疫沉淀（RIP）和染色质免疫沉淀（ChIP）实验检测SNHG12、磷酸酶和张力蛋白同源物（PTEN）与高迁移率族蛋白B1（HMGB1）之间的关系。最后，使用SNHG12腺病毒构建脱氢表雄酮（DHEA）诱导的PCOS小鼠，以探索其在PCOS中的作用。
与健康对照相比，PCOS患者GCs中SNHG12表达显著下调，且与糖酵解标志物呈正相关。功能研究表明，敲低SNHG12会损害KGN细胞的糖酵解，而SNHG12过表达可部分恢复糖酵解。此外，SNHG12诱导的糖酵解影响KGN细胞凋亡，通过乳酸生成和凋亡途径介导卵泡发育异常。腺病毒介导的SNHG12过表达减轻了PCOS小鼠的症状。机制上，RIP和ChIP实验表明，SNHG12与HMGB1相互作用，通过阻止HMGB1与PTEN启动子结合抑制PTEN转录，从而促进KGN细胞的糖酵解。
我们的研究结果共同表明，SNHG12/HMGB1/PTEN轴通过调节GCs中糖酵解介导的卵泡发育异常，在PCOS中作为一种新的调节机制，为PCOS提供了一个潜在的治疗靶点。
