CiRS-126 inhibits proliferation of ovarian granulosa cells through targeting the miR-21-PDCD4-ROS axis in a polycystic ovarian syndrome model

Abstract

Polycystic ovarian syndrome (PCOS) is considered to be one of the most prevalent endocrine disorders affecting women of reproductive age. CiRS-126, an innovative circular microRNA, has previously been proven to be a promising miR-21 sponge. However, a proper understanding of the impact of ciRS-126 on PCOS is needed. Circular RNA (CiRS) profiles were initially evaluated in ovarian cortex samples obtained from 18 women with PCOS as well from 9 women without PCOS. Insulin-induced ovarian granulosa cells isolated from mice were utilized for the functional study. CiRS microarray analysis and quantitative real-time PCR indicated that ciRs-126 expression was downregulated while miR-21 expression was upregulated in PCOS samples and insulin-induced granulosa cells as compared with non-PCOS samples and non-insulin-induced granulosa cells. Furthermore, ectopic overexpression of ciRS-126 was associated with a reduction in proliferation and increased apoptosis in insulin-treated granulosa cells. Meanwhile, bioinformatic prediction and the results of the dual-luciferase reporter assay indicated the presence of consecutive binding in the ciRS-126-miR-21-programmed cell death protein 4 (PDCD4) axis. Moreover, overexpression of miR-21 blocked ciRS-126 repression of proliferation and triggered the death of insulin-induced granulosa cells. Excessive PDCD4 expression counteracted the influence of miR-21 on cell death and proliferation. The data indicated that PDCD4 played a regulatory role in ROS generation, which is reportedly involved in apoptosis. Therefore, ciRS-126 reduction in PCOS granulosa cells targeted the miR-21-PDCD4 axis to reduce proliferation and promote apoptosis. CiRS-126 shows potential as a promising predictor of clinical outcome as well as a therapeutic target in PCOS.

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Funding

This study was funded by the National Science Foundation for Young Scientists of China (grant number 81801478; 61801108); the Suzhou Key Medical Center (grant number SZZX201505); the Jiangsu Maternal and Children Health Care Research Project (grant number F201603); the Jiangsu Provincial Medical Innovation Team (grant number CXTDB2017013); the Suzhou Clinical Medical Expert Team (grant number SZYJTD201708); the Jiangsu Maternal and Children Health Care Key Discipline (grant number FXK201748); the Suzhou Clinical Diagnosis and Treatment Technology (grant number LCZX201411); the Science and Technology Development Fund of Nanjing Medical University (grant number 2017NJMU158); and the Suzhou Science and Technology Support Program (grant number SYS201649).

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Correspondence to Ting Wang or Hong Li.

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Lu, J., Xue, Y., Wang, Y. et al. CiRS-126 inhibits proliferation of ovarian granulosa cells through targeting the miR-21-PDCD4-ROS axis in a polycystic ovarian syndrome model. Cell Tissue Res 381, 189–201 (2020). https://doi.org/10.1007/s00441-020-03187-9

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Keywords

  • PCOS
  • ciRS-126
  • miR-21
  • PDCD4
  • Apoptosis
  • ROS