Department of Gynecology and Gynecological Oncology, Inselspital, Bern University Hospital, University of Bern, Friedbuehlstrasse 19, 3010, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Murtenstrasse 35, 3008, Bern, Switzerland.
Department of Gynecology and Gynecological Oncology, Inselspital, Bern University Hospital, University of Bern, Friedbuehlstrasse 19, 3010, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Murtenstrasse 35, 3008, Bern, Switzerland.
J Steroid Biochem Mol Biol. 2021 Sep;212:105943. doi: 10.1016/j.jsbmb.2021.105943. Epub 2021 Jun 16.
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.
子宫内膜异位症是一种常见的雌激素依赖性疾病，其中子宫内膜组织在腹腔内生长。这些病变常表达低水平的孕激素受体（PR），这可能在孕激素治疗反应不足中发挥重要作用。在这里，我们揭示了下调的 PR 表达与子宫内膜异位症病变中的上皮间质转化（EMT）之间的相互关系。通过免疫组织化学染色，异位上皮腺体（93.1%，n=67/72）的大多数显示出 EMT 的异质状态。有趣的是，PR 表达水平低与 EMT 的标志 N-钙粘蛋白表达水平高相关。为了获得机制见解，我们使用子宫内膜异位症上皮细胞系 EM'osis 和 12Z 进行了体外功能测定。TGF-β诱导的 EMT，以 CDH2 和 SNAI1/2 的升高为标志，导致这两个细胞系中 PR 基因表达显著下调。相比之下，在 EM'osis 中沉默 SNAI1 和在 12Z 中沉默 SNAI1 和 SNAI2 显著增加了 PR 基因表达。我们发现，不仅在体外，而且在子宫内膜异位症病变的上皮成分中，SNAI1/2 的强表达与 PR 的弱表达相一致。总之，这些结果表明，子宫内膜异位症病变中 EMT 的异质状态与 PR 表达受抑制之间存在负相关关系。我们的功能测定表明，EMT 通过 EMT-TFs（如 SNAI1 和 SNAI2）的上调导致 PR 表达下调，这可能最终导致孕激素抵抗。
