Abstract
Endometriosis is a common, estrogen-dependent disease, in which endometrial tissue grows in the peritoneal cavity. These lesions often express low levels of progesterone receptors (PR), which potentially play an important role in the insufficient response to progestin treatment. Here, we uncover an interconnection between the downregulated PR expression and the epithelial-to-mesenchymal transition (EMT) in endometriotic lesions. The majority of ectopic epithelial glands (93.1 %, n = 67/72) display heterogeneous states of EMT by immunohistochemistry staining. Interestingly, low PR expression associated with high N-cadherin expression, a hallmark of EMT. In order to gain mechanistic insights, we performed in vitro functional assays with the endometriotic epithelial cell lines EM’osis and 12Z. TGF-β-induced EMT, marked by elevations of CDH2 and SNAI1/2, led to a significant downregulation of PR gene expression in both cell lines. In contrast, silencing of SNAI1 in EM’osis and of SNAI1 plus SNAI2 in 12Z elevated PR gene expression significantly. We found that not only in vitro, but also in the epithelial component of endometriotic lesions strong expression of SNAI1/2 concurred with weak expression of PR. In summary, these results suggested the negative correlation association of the heterogeneous states of EMT and suppressed PR expression in endometriotic lesions. Our functional assays indicate that EMT contributes to the downregulation of PR expression via the upregulation of EMT-TFs, like SNAI1 and SNAI2, which may ultimately lead to progesterone resistance.
Highlights
Endometriosis is a common gynecological disease affecting around 6-10 % of women of reproductive age, causing pelvic pain and infertility [1]
The protein expressions of E-cadherin and N-cadherin in ectopic epithelial cells was quantified by IHC in three subtypes of endometriosis: endometrioma (n = 4), superficial endometriosis (n = 3) and deeply infiltrating endometriosis (n = 4)
We found that the high protein expression of Snail family transcriptional repressor 1 (SNAI1)/2 in the ectopic epithelial cells associates with the low protein expression of progesterone receptors (PR), while the low protein expression of SNAI1/2 was concurrent with the high protein expression of PR
Summary
Endometriosis is a common gynecological disease affecting around 6-10 % of women of reproductive age, causing pelvic pain and infertility [1]. The basic rationale of the current medical therapies for endometriosis is to reduce estrogen level. Progestins, known for their anti-estrogenic effects resulting in endometrial decidualization, and inhibit the surges of gonadotropin-releasing hormone / luteinizing hormone [3, 4] and thereby block the ovulation. The treatment failure for endometriosis patients under o progestin-based therapy is increasingly noticed, potentially involving an attenuated response r to progestin treatments termed progesterone resistance [6, 7]. Progestins exert their effects by p binding to progesterone receptors (PR).
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