Plasminogen activator inhibitor-1 (PAI-1) expression in endometriosis

Abstract

Purpose Deep infiltrating endometriosis (DIE) is defined as an endometriotic lesion penetrating to a depth of >5 mm and is associated with pelvic pain, but the underlying mechanisms are unclear. Our objective is to investigate whether plasminogen activator inhibitor-1 expression (PAI-1) in endometriotic tissues is increased in women with DIE. Methods In this blinded in vitro study, immunohistochemistry and Histoscore were used to examine the expression of PAI-1 in glandular epithelium (GECs) and stroma (SCs) in a total of 62 women: deep infiltrating uterosacral/rectovaginal endometriosis (DIE; n = 13), ovarian endometrioma (OMA; n = 14), superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP; n = 23), uterine (eutopic) endometrium from women with endometriosis (UE; n = 6), and non-endometriosis eutopic endometrium (UC; n = 6). The following patient characteristics were also collected: age, American Fertility Society stage, hormonal suppression, phase of menstrual cycle, dysmenorrhea score and deep dyspareunia score. Results PAI-1 expression in GECs and SCs of the DIE group was significantly higher than that of SUP group (p = 0.01, p = 0.01, respectively) and UE group (p = 0.03, p = 0.04, respectively). Interestingly, increased PAI-1 expression in GECs and SCs was also significantly correlated with increased dysmenorrhea (r = 0.38, p = 0.01; r = 0.34, p = 0.02, respectively). Conclusions We found higher expression of PAI-1 in DIE, and an association between PAI-1 and worse dysmenorrhea.

ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

“…This system regulates extracellular fibrin proteolysis and influences cell invasion, migration, and ECM remodeling ( Duffy, 2004 ). SERPINE1 is a biomarker for endometriosis, with high levels of expression observed in ovarian and deep infiltrating endometriosis ( Alotaibi et al, 2019 ; Gilabert-Estellés et al, 2003 ; Ramón et al, 2005 ; Ye et al, 2017 ). We examined a published RNA-seq dataset of human endometrial organoids and observed that SERPINE1 was upregulated in organoids derived from ectopic endometrial tissue compared to healthy endometrial tissue (log 2 fold change [FC] = 3.86, FDR = 0.051) ( Boretto et al, 2019 ).…”

“…LtfCre 0/+ ; (Gt) R26 Pik3ca*H1047R ; Arid1a fl/fl eutopic endometrial epithelia and ectopic lesions showed increased SERPINE1 by IHC, which was not observed in LtfCre 0/+ ; (Gt)R26 Pik3ca*H1047R ; Arid1a fl/fl ; Ep300 fl/fl ( Figures 7G and 7H ). Among a cohort of deep infiltrating and ovarian endometriosis tissue samples ( Alotaibi et al, 2019 ), samples with a loss of ARID1A expression displayed the highest expression of SERPINE1 by IHC ( Figures S6A and S6B ).…”

“…SERPINE1 promoter polymorphisms linked to high levels of PAI-1 expression have been reported in endometriosis ( Bedaiwy et al, 2006 ; Ramón et al, 2005 ). Relative to other types of endometriosis, PAI-1 expression is increased in deep infiltrating ( Alotaibi et al, 2019 ) and ovarian endometriosis ( Gilabert-Estellés et al, 2003 ; Ramón et al, 2005 ). ARID1A mutations exist in both deep infiltrating and ovarian endometriosis ( Anglesio et al, 2017 ; Suda et al, 2018 ), and our clinical cohort suggests that ARID1A loss leads to PAI-1 overexpression in endometriosis.…”

“…For human endometriosis tissue samples, SERPINE1 (PAI-1) IHC was carried out as published (Alotaibi et al, 2019). Briefly, IHC using the EnVision+ Dual Link system (Dako) and 3,3-diaminobenzidine (DAB) was performed, using mouse monoclonal PAI-1 antibody C-9 (sc 5297, Santa Cruz).…”

“…(Figures 7G and 7H). Among a cohort of deep infiltrating and ovarian endometriosis tissue samples (Alotaibi et al, 2019), samples with a loss of ARID1A expression displayed the highest expression of SERPINE1 by IHC ( Figures S6A and S6B).…”