MicroRNA-135a Regulates VEGFC Expression and Promotes Luteinized Granulosa Cell Apoptosis in Polycystic Ovary Syndrome

Abstract

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.

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Funding

This work was supported in part by grants from the Shanghai Commission of Science and Technology (17DZ2271100), Program of Shanghai Academic Research Leader in Shanghai Municipal Commission of Health and Family Planning (No. 2017BR015), Shanghai Technological Innovation Plan (No. 18140902400), National Natural Science Foundation of China (No. 81901442), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20161413).

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Yifang Wei and Yu Hu designed and performed experiments and wrote the original draft manuscript, Shenglian Lu collected the clinical samples, Li Guo and Xiaoyu Wu analyzed the data, Xing Liu performed experiments, and Yun Sun oversaw the entire study and edited the manuscript.

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Correspondence to Yifang Wei or Yun Sun.

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Wei, Y., Lu, S., Hu, Y. et al. MicroRNA-135a Regulates VEGFC Expression and Promotes Luteinized Granulosa Cell Apoptosis in Polycystic Ovary Syndrome. Reprod. Sci. 27, 1436–1442 (2020). https://doi.org/10.1007/s43032-020-00155-0

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Keywords

  • miR-135a
  • PCOS
  • VEGFC
  • Apoptosis