Objective: To investigate the role and underlying mechanism of sigma-1 receptor (SigmaR1)/high mobility group A1 (HMGA1) in the pathogenesis of diminished ovarian reserve (DOR).
Design: In vitro cell experimental study.
Setting: The Reproductive Medical Center, People's Hospital of Zhengzhou University.
Sample: Serum, follicular fluid (FF), ovarian granulosa cells (GCs) and KGN cells.
Methods: Samples were collected from DOR patients. Endoplasmic reticulum (ER) stress was induced in the GCs using thapsigargin (TG). mRNA and protein levels were determined using reverse transcription-quantitative polymerase chain reaction and western blotting. Cell apoptosis and viability were assessed using flow cytometry and cell counting kit-8. Protein colocalization was detected via immunofluorescence. Molecular interactions were validated using co-immunoprecipitation, luciferase reporter and chromatin immunoprecipitation assays.
Main outcome measures: Cell viability, cell apoptosis, SigmaR1, HMGA1 and ER stress-associated mRNA levels.
Results: SigmaR1 expression decreased while HMGA1 expression increased in the serum, FF and GC samples of DOR patients and TG-treated GCs. TG induced ER stress and GC apoptosis; these effects were diminished by SigmaR1 overexpression or HMGA1 silencing. SigmaR1 expressed in the nuclear envelope forms a complex with gene repressor-specific protein 3 (SP3) and histone deacetylase (HDAC)1/2/3; however, TG reduced SigmaR1 in GCs and blocked the complex formation. HMGA1, a transcriptional target of SP3, was negatively modulated by the SigmaR1/SP3 complex. HMGA1 overexpression abolished the protective effect of SigmaR1 on TG-induced ER stress and GC apoptosis.
Conclusion: SigmaR1 formed a SmigaR1/SP3/HDAC complex to inhibit HMGA1 transcription, alleviating ER stress and GC apoptosis and providing new therapeutic targets for DOR.
Keywords: HMGA1; SigmaR1; diminished ovarian reserve; endoplasmic reticulum stress; granulosa cell apoptosis.
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