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.

中文翻译：

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减少的microRNA-125b-5p通过靶向小鼠前腔卵泡中的PAK3 / ERK1 / 2信号传导来破坏卵泡类固醇生成。

背景技术高雄激素血症是多囊卵巢综合征（PCOS）的主要特征之一。已在多种疾病中证实了miR-125b-5p表达异常，但是尚不清楚miR-125b-5p是否与窦前卵泡中的类固醇生成异常有关。方法在PCOS患者的临床血清样本中测量立体激素浓度和miR-125b-5p表达。使用小鼠前卵泡培养模型和来曲唑诱导的PCOS小鼠模型，我们研究了miR-125b-5p调节雄激素和雌激素分泌的潜在机制。结果在高雄激素性PCOS（HA-PCOS）患者的血清中观察到miR-125b-5p表达降低。在小鼠的窦前卵泡中 抑制miR-125b-5p可增加雄激素合成相关基因的表达并刺激睾丸激素的分泌，同时下调雌激素合成相关基因并降低雌二醇释放。异位表达的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。机理研究确定Pak3是miR-125b-5p的直接靶标。此外，抑制miR-125b-5p促进了小鼠前腔卵泡中ERK1 / 2的激活，而抑制Pak3则废除了这种激活作用。在来曲唑诱导的PCOS小鼠卵巢中概括了这些结果。值得注意的是，抑制PAK3拮抗miR-125b-5p siRNA对雄激素合成相关酶表达和睾丸激素分泌的积极作用。黄体生成素（LH）抑制miR-125b-5p表达，并刺激Pak3表达。结论PCOS患者中较高的血清LH浓度会抑制miR-125b-5p表达，从而进一步增加Pak3表达，导致ERK1 / 2信号激活，从而刺激HA-PCOS中雄激素合成相关酶的表达和睾丸激素的分泌。