Brain-derived neurotrophic factor promotes human granulosa-like tumor cell steroidogenesis and proliferation by activating the FSH receptor-mediated signaling pathway

Min Xie,Jun Jing,Ji Zhou,Xiaomeng Ding,Bing Yao,Meiling Li,Yidan Shao,Yuxiu Liu

doi:10.1038/s41598-017-00203-x

Abstract

Brain-derived neurotrophic factor (BDNF) and FSH receptor (FSHR) are expressed in ovarian granulosa cells, and play important roles in regulating follicle growth and oocyte maturation. Studies have linked the BDNF-associated signaling pathway to FSHR mRNA expression in the regulation of follicle development, but the mechanisms remain unknown. In the current study, we found that BDNF stimulated the secretion of estradiol and progesterone, and increased the proliferation of KGN cells (human granulosa-like tumor cell line). BDNF treatment also increased phosphorylated and ubiquitinated FSHR, and activated cAMP/PKA/CREB signaling pathway. Moreover, inhibition of BDNF expression by siRNA markedly reduced the estradiol secretion and down-regulated FSHR, aromatase and phosphorylated CREB; meanwhile, FSH treatment partly alleviated the effects of BDNF siRNA on KGN cells. These findings suggested that BDNF modulates graunlosa cell functions and the action probably mediated by FSHR-coupled signaling pathway, to affect aromatase-mediated steroidogenesis. These results provide an alternative target to optimize ovarian granulosa cell function.

Highlights

Brain-derived neurotrophic factor (BDNF) and FSH receptor (FSHR) are expressed in ovarian granulosa cells, and play important roles in regulating follicle growth and oocyte maturation
KGN cells were treated with FSH, and increased BDNF protein level was found in lysates (427.4 ± 18.9 pg/ml) and cell culture supernatants (102.8 ± 11.9 pg/ml) (Fig. 1), indicating that BDNF secretion was stimulated by gonadotrophin
These results demonstrated that KGN cells have common characteristics of normal human granulosa cells, i.e. production and secretion of BDNF

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) and FSH receptor (FSHR) are expressed in ovarian granulosa cells, and play important roles in regulating follicle growth and oocyte maturation. Inhibition of BDNF expression by siRNA markedly reduced the estradiol secretion and down-regulated FSHR, aromatase and phosphorylated CREB; FSH treatment partly alleviated the effects of BDNF siRNA on KGN cells. These findings suggested that BDNF modulates graunlosa cell functions and the action probably mediated by FSHR-coupled signaling pathway, to affect aromatase-mediated steroidogenesis. These results provide an alternative target to optimize ovarian granulosa cell function. By coupling these pathways, the indispensable functions of FSHR in granulosa cells could be performed[20]

Methods

Results

Conclusion