miR-125b-5p 表达下调通过靶向 PAK3/ERK1/2 信号通路破坏小鼠原始卵泡的类固醇生成。

Decreased microRNA-125b-5p disrupts follicle steroidogenesis through targeting PAK3/ERK1/2 signalling in mouse preantral follicles.

机构信息

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Department of Obstetrics and Gynaecology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.

出版信息

Metabolism. 2020 Jun;107:154241. doi: 10.1016/j.metabol.2020.154241. Epub 2020 Apr 15.

DOI:10.1016/j.metabol.2020.154241

PMID:32304754

Abstract

BACKGROUND

Hyperandrogenism is one of the major characteristics of polycystic ovary syndrome (PCOS). Abnormal miR-125b-5p expression has been documented in multiple diseases, but whether miR-125b-5p is associated with aberrant steroidogenesis in preantral follicles remains unknown.

METHODS

Steriod hormone concentrations and miR-125b-5p expression were measured in clinical serum samples from PCOS patients. Using a mouse preantral follicle culture model and a letrozole-induced PCOS mouse model, we investigated the mechanism underlying miR-125b-5p regulation of androgen and oestrogen secretion.

RESULTS

The decreased miR-125b-5p expression was observed in the sera from hyperandrogenic PCOS (HA-PCOS) patients. In mouse preantral follicles, inhibiting miR-125b-5p increased the expression of androgen synthesis-related genes and stimulated the secretion of testosterone, while simultaneously downregulating oestrogen synthesis-related genes and decreasing oestradiol release. Ectopically expressed miR-125b-5p reversed the effects on steroidogenesis-related gene expression and hormone release. Mechanistic studies identified Pak3 as a direct target of miR-125b-5p. Furthermore, inhibiting miR-125b-5p facilitated the activation of ERK1/2 in mouse preantral follicles, while inhibiting Pak3 abrogated this activating effect. These results were recapitulated in letrozole-induced PCOS mouse ovaries. Of note, inhibiting PAK3 antagonised the positive effect of miR-125b-5p siRNA on the expressions of androgen synthesis-related enzymes and testosterone secretion. Luteinizing hormone (LH) inhibited miR-125b-5p expression, and stimulated Pak3 expression.

CONCLUSION

High serum LH concentrations in PCOS patients repress miR-125b-5p expression, which further increases Pak3 expression, leading to activation of ERK1/2 signalling, thus stimulating the expression of androgen synthesis-related enzymes and testosterone secretion in HA-PCOS.

摘要

背景

高雄激素血症是多囊卵巢综合征（PCOS）的主要特征之一。miR-125b-5p 的异常表达已在多种疾病中得到证实，但 miR-125b-5p 是否与窦前卵泡中异常的类固醇生成有关尚不清楚。

方法

测量多囊卵巢综合征患者临床血清样本中的类固醇激素浓度和 miR-125b-5p 表达。使用小鼠窦前卵泡培养模型和来曲唑诱导的多囊卵巢综合征小鼠模型，研究了 miR-125b-5p 调节雄激素和雌激素分泌的机制。

结果

在高雄激素的多囊卵巢综合征（HA-PCOS）患者的血清中观察到 miR-125b-5p 表达降低。在小鼠窦前卵泡中，抑制 miR-125b-5p 增加了雄激素合成相关基因的表达并刺激了睾酮的分泌，同时下调了雌激素合成相关基因并减少了雌二醇的释放。外源性表达 miR-125b-5p 逆转了对类固醇生成相关基因表达和激素释放的影响。机制研究表明 Pak3 是 miR-125b-5p 的直接靶标。此外，抑制 miR-125b-5p 促进了小鼠窦前卵泡中 ERK1/2 的激活，而抑制 Pak3 则阻断了这种激活作用。这些结果在来曲唑诱导的多囊卵巢综合征小鼠卵巢中得到了重现。值得注意的是，抑制 PAK3 拮抗了 miR-125b-5p siRNA 对雄激素合成相关酶的表达和睾酮分泌的正向作用。促黄体生成素（LH）抑制 miR-125b-5p 的表达，并刺激 Pak3 的表达。