Nuclear Receptor Subfamily 4 Group A Member 3: A Potential Marker of Endometriosis.

Background: Nuclear receptor subfamily 4 group A member 3 (NR4A3) is lowly expressed in ectopic endometrium and can be degraded by ubiquitination in vascular endothelial cells. Murine double minute 2 (MDM2) is predicted to be the ubiquitin ligase of NR4A3. Hence, we investigated the effects of NR4A3 and MDM2 on endometriosis and clarified corresponding regulatory mechanisms.

Methods: The ubiquitin ligase of NR4A3 was predicted using bioinformatics and validated by immunoprecipitation. The effects of NR4A3 and MDM2 on the migration and proliferation of human endometrial stromal cells (hESCs) were examined by Transwell assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. NR4A3 and MDM2 expressions were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. An endometriosis model was constructed in Sprague-Dawley rats, followed by body weight analysis, ultrasonic imaging of ectopic cysts, and Western blot.

Results: Overexpression of NR4A3 inhibited, but siNR4A3 boosted hESC migration and proliferation. MDM2 promoted NR4A3 ubiquitination and degradation. MDM2 overexpression enhanced hESC migration and proliferation and partially reversed the inhibitory effect of NR4A3 overexpression. Overexpression of NR4A3 reduced ectopic cysts in endometriotic rats, which was offset by MDM2 overexpression.

Conclusion: NR4A3, which is promoted to ubiquitination and degradation by MDM2, inhibits the proliferation and migration of hESCs in vitro, and reduces the growth of ectopic endometrial cysts in vivo, thereby inhibiting the progression of endometriosis.