Research Paper Volume 13, Issue 3 pp 4617—4633

LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway

Min Tan1, *, , Yanxiang Cheng2, *, , Xiaozhu Zhong1, , Dongyong Yang2, , Sushi Jiang1, , Yang Ye1, , Miao Ding1, , Guijun Guan3, , Dongzi Yang1, , Xiaomiao Zhao1, ,

  • 1 Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
  • 2 Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
  • 3 Shanghai Collaborative Innovation for Aquatic Animal Genetics and Breeding, College of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai 201306, China
* Co-first authors

Received: October 3, 2020       Accepted: November 17, 2020       Published: January 20, 2021
How to Cite

Copyright: © 2021 Tan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Polycystic ovary syndrome (PCOS), which is often accompanied by insulin resistance, is closely related to increased apoptosis of ovarian granulosa cells. LNK is an important regulator of the insulin signaling pathway. When insulin binds to the receptor, the PI3K/AKT/FOXO signaling pathway is activated, and FOXO translocates from the nucleus to the cytoplasm, thereby inhibiting the expression of pro-apoptotic genes.

Methods: Granulosa cells were collected from PCOS patients to investigate the relationship between LNK, cell apoptosis and insulin resistance. KGN cells underwent LNK overexpression/silence and insulin stimulation. The AKT/FOXO3 pathway was studied by western blot and immunofluorescence. LNK knockout mice were used to investigate the effect of LNK on the pathogenesis of PCOS.

Results: The level of LNK was higher in PCOS group than control group. LNK was positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with oocyte maturation rate. LNK overexpression in KGN cells inhibited insulin-induced AKT/FOXO3 signaling pathway, causing nucleus translocation of FOXO3 and promoting granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice.

Conclusions: LNK was closely related to insulin resistance and apoptosis of granulosa cells via the AKT/FOXO3 pathway. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice, suggesting LNK might become a potential biological target for the clinical treatment of PCOS.


PCOS: polycystic ovary syndrome; GC: granulosa cell; BMI: body mass index; WC: waist circumference; WHR: waist-hip ratio; FPG: fasting plasma glucose; FIN: fasting insulin; HOMA-IR: homeostasis model assessment for insulin resistance; FOXO3: forkhead box class O3; GLUT4: glucose transporter 4; FSHR: follicle stimulating hormone receptor; LHR: luteinizing hormone receptor; AMHR: anti-Mullerian hormone type 2 receptor; CYP19: cytochrome P450 family 19; AR: androgen receptor; HFD: high fat diet; NIH: National Institutes of Health.