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

Ma, Lijuan; Andrieu, Thomas; McKinnon, Brett; Duempelmann, Lea; Peng, Ren‐Wang; Wotzkow, Carlos; Müller, Christoph; Mueller, Christoph

doi:10.1016/j.jsbmb.2021.105943

Cited by 18 publications

(10 citation statements)

References 46 publications

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“…Based on these observations, we evaluated senescence and EMT markers using immuhistochemistry in endometrial specimens. Consistent with the previous studies 6 , epithelial cells in ectopic lesions showed a decrease of E- cadhein (a hallmark of EMT) and an increase of vimentin (mesenchymal marker). In contrast, the expression of senescence markers including β-gal, p16 and p38 MAPK were decreased in ectopic lesions compared to normal and eutopic endometriotic lesions (Fig.…”

Section: Resultssupporting

confidence: 91%

“…EMT is a process by which epithelial cells convert to motile mesenchymal cells. This mostly occurs during embryonic development and cancer and has been found in endometrial epithelial cells in vitro and in human endometrial tissues 6 . Once the ectopic endometriotic lesion is established, multiple mechanisms involved with EMT are activated, resembling cancer-like progression and invasive growth 7 .…”

Section: Introductionmentioning

confidence: 99%

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SIRT1 upregulation promotes epithelial-mesenchymal transition by inducing senescence escape in endometriosis

Wang

et al. 2022

Sci Rep

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Endometrial epithelial cells carry distinct cancer-associated alterations that may be more susceptible to endometriosis. Mouse models have shown that overexpression of SIRT1 associated with oncogene activation contributes to the pathogenesis of endometriosis, but the underlying reason remains elusive. Here, we used integrated systems biology analysis and found that enrichment of endometrial stromal fibroblasts in endometriosis and their cellular abundance correlated negatively with epithelial cells in clinical specimens. Furthermore, endometrial epithelial cells were characterized by significant overexpression of SIRT1, which is involved in triggering the EMT switch by escaping damage or oncogene-induced induced senescence in clinical specimens and in vitro human cell line models. This observation supports that genetic and epigenetic incident favors endometrial epithelia cells escape from senescence and fuel EMT process in endometriosis, what could be overcome by downregulation of SIRT1.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

SIRT1 upregulation promotes epithelial-mesenchymal transition by inducing senescence escape in endometriosis

Wang

et al. 2022

Sci Rep

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“…The immunohistochemical and bioinformatic analysis found that EMT-related biomarkers are significantly altered in ectopic endometrial tissues relative to the eutopic tissues ( Chen et al, 2020 ; Konrad et al, 2020 ). More importantly, EMT serves as a critical biological step for endometriosis progression, because EMT results in a more aggressive capacity of the endometriotic cells (increased MMPs), leading to progesterone resistance (down-regulation of progesterone receptor) and triggering the formation of fibrosis ( Zhang et al, 2016 ; Zondervan et al, 2018 ; Ma et al, 2021 ). As reviewed by Yan-Meng Yang and Wan-Xi Yang, hypoxia and estrogen initiate the EMT through different pathways (TGF-β/Smad and Wnt/β-catenin, etc.)…”

Section: Discussionmentioning

confidence: 99%

Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression

Yang

Zhao

et al. 2022

Front. Pharmacol.

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Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.

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“…Endometriotic lesion tissue also displays progesterone resistance and altered gene expression [ 9 ], and this is proposed to be at least in part due to altered progesterone receptor (PGR) expression. Mechanistically, studies suggest that this misexpression may be due to altered AKT and/or MEK 1/2 activity [ 10 ], the inflammatory milieu associated with the disease [ 11 ], and/or epithelial-to-mesenchymal transition [ 12 ]. Taken together, both eutopic and ectopic endometrial tissue exhibit altered progesterone responsiveness, and this may in part be due to the altered expression of PGRs.…”

Section: Endometriosis: Steroid Dependency and Resistancementioning

confidence: 99%

MicroRNAs and Progesterone Receptor Signaling in Endometriosis Pathophysiology

Nothnick

2022

Cells

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Endometriosis is a significant disease characterized by infertility and pelvic pain in which endometrial stromal and glandular tissue grow in ectopic locations. Altered responsiveness to progesterone is a contributing factor to endometriosis pathophysiology, but the precise mechanisms are poorly understood. Progesterone resistance influences both the eutopic and ectopic (endometriotic lesion) endometrium. An inability of the eutopic endometrium to properly respond to progesterone is believed to contribute to the infertility associated with the disease, while an altered responsiveness of endometriotic lesion tissue may contribute to the survival of the ectopic tissue and associated symptoms. Women with endometriosis express altered levels of several endometrial progesterone target genes which may be due to the abnormal expression and/or function of progesterone receptors and/or chaperone proteins, as well as inflammation, genetics, and epigenetics. MiRNAs are a class of epigenetic modulators proposed to play a role in endometriosis pathophysiology, including the modulation of progesterone signaling. In this paper, we summarize the role of progesterone receptors and progesterone signaling in endometriosis pathophysiology, review miRNAs, which are over-expressed in endometriosis tissues and fluids, and follow this with a discussion on the potential regulation of key progesterone signaling components by these miRNAs, concluding with suggestions for future research endeavors in this area.

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

Cited by 18 publications

References 46 publications

SIRT1 upregulation promotes epithelial-mesenchymal transition by inducing senescence escape in endometriosis

SIRT1 upregulation promotes epithelial-mesenchymal transition by inducing senescence escape in endometriosis

Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression

MicroRNAs and Progesterone Receptor Signaling in Endometriosis Pathophysiology

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