NR5A2 increases inflammation and cell proliferation by regulating the nuclear factor κB pathway in polyendocrine metabolic ovarian syndrome.

RESEARCH QUESTION: Does NR5A2 (nuclear receptor subfamily 5 group A member 2) play a role in the dysregulation of granulosa cells in polyendocrine metabolic ovarian syndrome (PMOS), which is a common endocrine disorder and a leading cause of anovulatory infertility, and what are its underlying regulatory mechanisms?

DESIGN

The mRNA expression levels of NR5A2 and related genes were assessed in human granulosa cells (HGCs) isolated from patients with or without PMOS. To investigate the effects of NR5A2 on inflammation and proliferation of granulosa cells, as well as the underlying molecular mechanisms, in-vitro experiments were conducted using the KGN human granulosa-like cell line.

RESULTS

Overexpression of NR5A2 promoted cell proliferation and induced G1-to-S phase transition in KGN cells, at least in part by upregulating cyclin D1 (CCND1) expression. NR5A2 acted as a co-activator of NF-κB p65 (also known as RelA) by increasing its phosphorylation and nuclear localization, thereby increasing CCND1 expression through transcriptional regulation. Furthermore, NR5A2 regulated the IL-1β positive self-regulatory loop via the NF-κB p65 signalling pathway.

CONCLUSIONS

Up-regulated NR5A2 may contribute to chronic inflammation and aberrant proliferation of granulosa cells by increasing NF-κB p65 activity. These findings highlight NR5A2 as a potential therapeutic target for ameliorating ovarian dysfunction in patients with PMOS.