Epithelial-to-mesenchymal transition contributes to the downregulation of progesterone receptor expression in endometriosis lesions

Lijuan Ma, Thomas Andrieu, Brett McKinnon, Lea Duempelmann, Ren‐Wang Peng, Ren-Wang Peng, Carlos Wotzkow, Christoph Müller, Michael D Mueller, Christoph Mueller
The Journal of steroid biochemistry and molecular biology · 2021 · vol. 212 , pp. 105943 · doi:10.1016/j.jsbmb.2021.105943 · PMID:34144151 · W3167785827
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Epithelial-to-mesenchymal transition in endometriosis lesions is associated with low progesterone receptor expression, mediated by EMT-inducing transcription factors like SNAI1/2.

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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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Epithelial-Mesenchymal Transition Receptors, Progesterone Antigens, CD Antigens, CD Cadherins Cadherins Cell Line Down-Regulation Endometriosis Epithelial Cells Epithelial Cells Female Humans Receptors, Progesterone Snail Family Transcription Factors Snail Family Transcription Factors Snail Family Transcription Factors

Citation neighborhood (2-hop)

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

References (46)

Cited by (16)

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