Journal
JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS
Volume 6, Issue 4, Pages 196-211Publisher
SAGE PUBLICATIONS LTD
DOI: 10.5301/je.5000198
Keywords
Decidualization; Endometriosis; Epidermal growth factor receptor; Fibroblast; Mammalian target of rapamycin; Mitogen-activated protein kinase
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Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health (NICHD/NIH), Specialized Cooperative Centers Program in Reproduction and Infertility Research [U54HD 055764-06, F32HD074423]
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Purpose: Decidualization comprises specific biochemical and morphological changes in uterine endometrium essential for establishment of pregnancy. This process is abnormal in women with endometriosis, a disorder in which endometrial-like tissue is present outside the uterus. The aim of this study was to restore cAMP-induced decidualization marker expression in endometrial stromal fibroblasts from women with endometriosis by using chemical inhibitors to PI3K/AKT/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) signaling pathways in vitro. Methods: Endometrial stromal fibroblasts (eSF) from women with (eSF endo) and without (eSF non-endo) endometriosis were treated with inhibitors to EGFR tyrosine kinase (gefitinib), mTOR (rapamycin) and MAPK kinase 1/2 (MEK1/2) (UO126) during 8-bromoadenosine 3',5'-cyclic monophosphate (8-br-cAMP)-stimulated decidualization. Decidualization was assessed by evaluating expression of insulin growth factor binding protein 1 (IGFBP1), prolactin (PRL) and forkhead box protein O1A (FOXO1A) by quantitative real-time PCR. Results: Gefitinib restored expression of decidualization markers in eSF endo to levels consistent with those in eSF non-endo. Elevated levels of phosphorylated mTOR in eSF endo were reduced to levels found in eSF non-endo, by gefitinib during treatment with 8-br-cAMP. Additional gene expression analyses suggested dysregulation of EGFR negative feedback regulators in eSF endo. Conclusions: Results implicate EGFR signaling as an underlying cause for aberrant cAMP-induced decidualization in women with endometriosis, and provide a potential target for management of infertility associated with the disease. The reduction of p-mTOR levels in eSF endo during 8-br-cAMP treatment suggests cooperation between EGR and protein kinase A signaling in the regulation of mTOR in eSF.
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