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Follicular Fluid-Derived Exosomal MicroRNA-18b-5p Regulates PTEN-Mediated PI3K/Akt/mTOR Signaling Pathway to Inhibit Polycystic Ovary Syndrome Development

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Abstract

Small RNA sequences in follicular fluid (FF)-derived exosomes (extracellular vesicles contain proteins, DNA, and RNA) vitally function in the development of polycystic ovary syndrome (PCOS). It has been identified that microRNA (miR)-18b-5p is one of miRs that differ between control and PCOS women that passed the false discovery rate, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an important modifier of biological functions of ovarian granulosa cells (GCs) in PCOS. However, whether miR-18b-5p could functionally mediate the progression of PCOS via PTEN was not clarified completely, which was the issue we wanted to solve in our research. FF-derived exosomes were isolated using an extraction kit. KGN cells were co-cultured with miR-18b-5p-modified exosomes or transfected with a PTEN-related vector. After treatment, cell proliferation and apoptosis were observed. A rat model of PCOS was established by letrozole and then injected with miR-18b-5p-modified exosomes. Then, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and estradiol (E2) levels in PCOS rats were measured. miR-18b-5p, PTEN, and phosphatidylinositol 3 kinases/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway-related genes were tested. In PCOS patients, miR-18b-5p was downregulated, and PTEN was highly expressed in FF and GCs. PTEN knockdown increased KGN cell proliferation and limited apoptosis. FF-derived exosomes stimulated proliferation and suppressed apoptosis of KGN cells; decreased FSH, LH, and testosterone; and increased E2 in PCOS rats. Upregulating miR-18b-5p further enhanced the inhibitory effects of exosomes on suppressing the progression of PCOS. miR-18b-5p targeted PTEN and could activate PI3K/Akt/mTOR pathway. miR-18b-5p produced by FF-derived exosomes reduces PTEN expression and promotes the activation of the PI3K/Akt/mTOR signaling pathway to improve PCOS. Based on that, circulating miR-18b-5p levels can contribute to the progression of PCOS complications.

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Acknowledgements

We would like to acknowledge the reviewers for their helpful comments on this paper.

Funding

This work was supported by the Science and Technology Department of Hainan Province (2019RC389, ZDYF2017086, ZDYF2019157).

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Authors and Affiliations

  1. Reproductive Medical Center, Hainan Women and Children’s Medical Center, No.75 Longkun South Road, Haikou, 570206, Hainan, China

    Zhi Zhou, Zhihua Tu, Bangbei Wan, Yejuan Li, Anguo Wang, Liqiang Zhao, Jiajia Hu, Ning Ma, Jing Zhou, Lin Chen, Yanqin Song & Weiying Lu

  2. Reproductive Medical Center, Zhuzhou Central Hospital, Zhuzhou, 412007, Hunan, China

    Juan Zhang

  3. Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Can tan

  4. Yikon Genomics Co. Ltd., Suzhou, 215000, Jiangsu, China

    Xiaoyong Shen

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  1. Zhi Zhou
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Contributions

Weiying Lu contributed to study design; Zhi Zhou and Zhihua Tu contributed to manuscript editing; Juan Zhang, Can tan, Xiaoyong Shen, Bangbei Wan, and Yejuan Li contributed to experimental studies; Anguo Wang, Liqiang Zhao, Jiajia Hu, Ning Ma, Jing Zhou, Lin Chen, and Yanqin Song contributed to data analysis.

Corresponding author

Correspondence to Weiying Lu.

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Experimental approval was acquired from ethics committee of Hainan Women and Children’s Medical Center. Written informed consent was collected from all participants. The animal experiment was approved by the animal ethics committee of Hainan Women and Children’s Medical Center.

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Zhi Zhou and Zhihua Tu are co-first authors.

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Zhou, Z., Tu, Z., Zhang, J. et al. Follicular Fluid-Derived Exosomal MicroRNA-18b-5p Regulates PTEN-Mediated PI3K/Akt/mTOR Signaling Pathway to Inhibit Polycystic Ovary Syndrome Development. Mol Neurobiol 59, 2520–2531 (2022). https://doi.org/10.1007/s12035-021-02714-1

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