Up-regulated WNT5A in PCOS affects steroidogenesis, proliferation and apoptosis of granulosa cells through the PI3K/AKT pathway.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders in women of reproductive age and is characterized by a chronic state of excessive inflammation. Increased expression of WNT5A in a variety of diseases is thought to be related to inflammatory states. The purpose of this study was to explore the potential effects of WNT5A on ovarian granulosa cells and its potential role in the pathogenesis of PCOS. RESULTS: In this study, we found increased expression of WNT5A in the follicular fluid and granulosa cells (GCs) of PCOS patients undergoing in vitro fertilization-embryo transfer (IVF-ET). By constructing an animal model of PCOS, we verified the elevated expression of WNT5A and decreased expression of CYP19A1, a key enzyme for steroidogenesis, in the ovarian granulosa cells of PCOS mice compared with those of controls. LPS stimulation induced significant upregulation of WNT5A expression in human ovarian granulosa tumor (KGN) cells. WNT5A can inhibit KGN cell proliferation and promote KGN cell apoptosis, and overexpression of WNT5A can inhibit the expression of genes related to steroidogenesis and steroid hormone secretion in vitro. WNT5A can activate the PI3K/AKT signalling pathway. A PI3K/AKT pathway inhibitor (LY-294002) inhibited the effects of WNT5A on key steroidogenesis genes in KGN cells. CONCLUSIONS: WNT5A inhibits steroidogenesis via the PI3K/AKT pathway in granulosa cells. Our findings suggest that increased WNT5A may be attributed to inflammation and may result in endocrine dysregulation in PCOS patients.