Center for Reproductive Medicine, No. 455 Hospital of the Chinese People's Liberation Army, Second Military Medical University, Shanghai, 200052, China.
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, China.
Reprod Sci. 2020 Jul;27(7):1436-1442. doi: 10.1007/s43032-020-00155-0. Epub 2020 Feb 3.
Androgen is known to regulate microRNA-135a (miR-135a) and can be regulated by androgen, suggesting that it may contribute to polycystic ovary syndrome (PCOS) with hyperandrogenism. However, its roles and mechanisms of action in PCOS are unknown. In this study, the role and molecular mechanisms underlying miR-135a in granulosa cells (GCs) in PCOS were evaluated. miR-135a expression was upregulated in patients with PCOS and in GCs isolated from patients compared with that in the respective controls (P < 0.01), as determined by RT-qPCR. The overexpression of miR-135a inhibited GC proliferation and induced GC apoptosis, as observed by CCK-8 assay and apoptosis assay. Furthermore, miR-135a overexpression increased the expression of double-strand break maker, γH2AX, as confirmed by western blotting. Our results further suggest that these effects were mediated via downregulation of vascular endothelial growth factor C (VEGFC), which was identified as a direct target of miR-135a. Moreover, levels of VEGFC and miR-135a expression showed a negative correlation. These findings indicate that miR-135a promotes apoptosis and the DNA damage response in GCs in PCOS, likely via VEGFC signaling. This study provides novel insights into GC dysregulation in PCOS and suggests that miR-135a is a promising therapeutic target for PCOS treatment.
雄激素已知可调节 microRNA-135a（miR-135a），且可受雄激素调节，这表明其可能与高雄激素血症的多囊卵巢综合征（PCOS）有关。然而，其在 PCOS 中的作用和作用机制尚不清楚。在这项研究中，评估了 miR-135a 在多囊卵巢综合征颗粒细胞（GC）中的作用和分子机制。通过 RT-qPCR 确定，与各自的对照相比，PCOS 患者和从患者中分离的 GC 中 miR-135a 的表达上调（P < 0.01）。CCK-8 测定和凋亡测定表明，miR-135a 的过表达抑制 GC 增殖并诱导 GC 凋亡。此外，通过 Western blot 证实，miR-135a 过表达增加了双链断裂制造者 γH2AX 的表达。我们的研究结果进一步表明，这些作用是通过下调血管内皮生长因子 C（VEGFC）介导的，VEGFC 被鉴定为 miR-135a 的直接靶标。此外，VEGFC 和 miR-135a 表达水平呈负相关。这些发现表明，miR-135a 可能通过 VEGFC 信号促进 PCOS 中 GC 的凋亡和 DNA 损伤反应。这项研究为 PCOS 中 GC 失调提供了新的见解，并表明 miR-135a 是治疗 PCOS 的有前途的治疗靶点。
