Hypoxia-inducible factor 1α-induced epithelial–mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis

Xiong, Yao; Liu, Yi; Xiong, Wenqian; Zhang, Ling; Liu, Hengwei; Du, Yu; Li, Na

doi:10.1093/humrep/dew081

Cited by 79 publications

(62 citation statements)

References 39 publications

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“…Hypoxia was recently reported to induce EMT in endometriosis 17 . Increased EZH2 expression by hypoxia activates its downstream Wnt/β-catenin pathway in breast cancer 44 .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, to date several factors have been shown to regulate EMT in endometriosis and adenomyosis, including estrogen 11 , Wnt/β-catenin 2 , lipocalin 2 12 , hepatocyte growth factor (HGF) 2, 13, 14 , lysyl oxidase 15 , periostin 16 , hypoxia 17 , microRNA-200b (miR-200b) 18 , platelets 7 and possibly Myc 19 and LSD1 20 . It becomes clear that EMT not only increases cellular invasiveness but also promotes fibrogenesis 7, 21 .…”

Section: Introductionmentioning

confidence: 99%

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Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

Zhang

Dong

Liu

et al. 2017

Sci Rep

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EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity. Conversely, overexpression of EZH2 induced the expression of Snail, Slug and vimentin and suppresses E-cadherin expression. In vivo administration of 3-Deazaneplanocin A (DZNep), an EZH2 inhibitor, significantly inhibited the growth of endometriotic lesions and improved generalized hyperalgesia, along with attenuated EMT and reduced fibrosis in endometriosis. Notably, platelets induced EZH2 upregulation and increased H3K27 and H3K9 trimethylation levels in endometriotic epithelial cells. These data identify EZH2 as a novel driver of EMT in endometriosis, implicates the link between wound healing and epigenetic changes in the context of endometriosis, and underscore the role of platelets in the development of endometriosis.

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“…Hypoxia was recently reported to induce EMT in endometriosis 17 . Increased EZH2 expression by hypoxia activates its downstream Wnt/β-catenin pathway in breast cancer 44 .…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

Zhang

Dong

Liu

et al. 2017

Sci Rep

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“…Inhibiting TGF-βR enhances emMSC surface marker expression, promotes cell proliferation, and prevents apoptosis of emMSCs [208]. The inflammatory niche may also contribute to endometriosis, which is characterized by increased stabilization of HIF-1α and HIF-1α-induced expression of VEGF and MMP-9 in eutopic and ectopic endometria [209,210,211,212]. …”

Section: Cell-based Therapy For Endometriosis Treatmentmentioning

confidence: 99%

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

Lin

Chen

Chang

et al. 2018

IJMS

140

104

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Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.

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“…[525354] Hypoxia induces the EMT of endometrial cells, resulting in cellular characteristics changes, which may be a prerequisite for the establishment of endometriotic lesions. [55]…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-beta 1 Involved in the Pathogenesis of Endometriosis through Regulating Expression of Vascular Endothelial Growth Factor under Hypoxia

Yu¹,

Xiu

Chen

et al. 2017

Chinese Medical Journal

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Background:Endometriosis (EMs) is a common gynecological disorder characterized by endometrial-like tissue outside the uterus. Hypoxia induces the expression of many important downstream genes to regulate the implantation, survival, and maintenance of ectopic endometriotic lesions. Transforming growth factor-beta 1 (TGF-β1) plays a major role in the etiology of EMs. We aimed to determine whether TGF-β1 affects EMs development and progression and its related mechanisms in hypoxic conditions.Methods:Endometrial tissue was obtained from women with or without EMs undergoing surgery from October, 2015 to October, 2016. Endometrial cells were cultured and then exposed to hypoxia and TGF-β1 or TGF-β1 inhibitors. The messenger RNA (mRNA) and protein expression levels of TGF-β1, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF-1α) were measured. A Dual-Luciferase Reporter Assay was used to examine the effect of TGF-β1 and hypoxia on a VEGF promoter construct. Student's t-test was performed for comparison among groups (one-sided or two-sided) and a value of P < 0.05 was considered statistically significant.Results:TGF-β1, VEGF, HIF-1α mRNA, and protein expression were significantly higher in EMs tissue than that in normal endometrial tissue (t = 2.16, P = 0.042). EMs primary cultured cells exposed to hypoxia expressed 43.8% higher VEGF mRNA and protein (t = 6.84, P = 0.023). VEGF mRNA levels increased 12.5% in response to TGF-β, whereas the combined treatment of hypoxia/TGF-β1 resulted in a much higher production (87.5% increases) of VEGF. The luciferase activity of the VEGF promoter construct was increased in the presence of either TGF-β1 (2.6-fold, t = 6.08, P = 0.032) or hypoxia (11.2-fold, t = 32.70, P < 0.001), whereas the simultaneous presence of both stimuli resulted in a significant cooperative effect (18.5-fold, t = 33.50, P < 0.001).Conclusions:The data support the hypothesis that TGF-β1 is involved in the pathogenesis of EMs through regulating VEGF expression. An additive effect of TGF-β1 and hypoxia is taking place at the transcriptional level.

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Hypoxia-inducible factor 1α-induced epithelial–mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis

Abstract: This study was funded by the National Nature Science Foundation of China (grant number 81170545 and 81471439). The authors declare no competing interests.

Cited by 79 publications

References 39 publications

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

Transforming Growth Factor-beta 1 Involved in the Pathogenesis of Endometriosis through Regulating Expression of Vascular Endothelial Growth Factor under Hypoxia

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