Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China.
J Cell Physiol. 2020 Nov;235(11):8826-8838. doi: 10.1002/jcp.29725. Epub 2020 May 11.
Distinct microRNA (miRNA) profiles have been reported in premature ovarian insufficiency (POI), but their functional relevance in POI is not yet clearly stated. In this study, aberrant expressions of miR-127-5p and high mobility group box 2 (HMGB2) were observed by microarrays in granulosa cells (GCs) from biochemical POI (bPOI) women and further confirmed by a quantitative reverse-transcription polymerase chain reaction. Immortalized human granulosa cell line and mouse primary ovarian GCs were used for functional validation. Orthotopic mouse model was established to examine the role of miR-127-5p in vivo. Finally, the expression of miR-127-5p was measured in the plasma of bPOI women. The receiver operating characteristic curve analysis was performed to determine the indicative role of miR-127-5p for ovarian reserve. Results showed the upregulation of miR-127-5p was identified in GCs from bPOI patients. It inhibited GCs proliferation and impaired DNA damage repair capacity through targeting HMGB2, which was significantly downregulated in GCs from the same cohort of cases. miR-127-5p was confirmed to attenuate DNA repair capability via HMGB2 in mouse ovary in vivo. Intriguingly, the upexpression of miR-127-5p was also detected in plasma of bPOI individuals, suggesting that miR-127-5p could be a promising indicator for bPOI. Taken together, our results discovered the deleterious effects of miR-127-5p on GCs function and its predictive value in POI process. The target gene HMGB2 could be considered as a new candidate for POI. This study highlights the importance of DNA repair capacity for ovarian function and sheds light on the epigenetic mechanism in the pathogenicity of POI.
已有研究报道，在卵巢早衰（POI）患者中存在不同的微小 RNA（miRNA）表达谱，但它们在 POI 中的功能相关性尚不清楚。本研究通过微阵列技术观察到生物化学 POI（bPOI）患者的颗粒细胞（GCs）中 miR-127-5p 和高迁移率族蛋白 2（HMGB2）的表达异常，并通过定量逆转录聚合酶链反应进一步证实。本研究使用永生化人颗粒细胞系和小鼠原代卵巢 GCs 进行功能验证，建立了原位小鼠模型以研究 miR-127-5p 在体内的作用，最后测量了 bPOI 女性血浆中 miR-127-5p 的表达。通过接受者操作特征曲线分析来确定 miR-127-5p 对卵巢储备的指示作用。结果显示，bPOI 患者的 GCs 中发现 miR-127-5p 上调。它通过靶向 HMGB2 抑制 GCs 增殖并损害 DNA 损伤修复能力，而在同一病例队列的 GCs 中 HMGB2 明显下调。miR-127-5p 被证实通过 HMGB2 减弱了小鼠卵巢中的 DNA 修复能力。有趣的是，还在 bPOI 个体的血浆中检测到 miR-127-5p 的高表达，表明 miR-127-5p 可能是 bPOI 的一个有前途的指标。总之，本研究发现 miR-127-5p 对 GCs 功能具有有害影响及其在 POI 过程中的预测价值。靶基因 HMGB2 可被视为 POI 的新候选基因。本研究强调了 DNA 修复能力对卵巢功能的重要性，并阐明了 POI 发病机制中的表观遗传机制。
