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The programmed death-1 (PD-1)/PD-L1 pathway plays important roles in immune responses and peripheral tolerance. Under pathological conditions, this pathway can suppress protective T cell responses and induce immune system disorders. Endometriosis (EM) is an estrogen-dependent, immune-associated disease. The expression of PD-1 and PD-L1 has been studied in a variety of cancers and autoimmune diseases. Few studies, however, have attempted to explore their expression and the possibility that they are regulated by estrogen in EM. Eutopic and ectopic endometria and blood samples were collected from 15 women with EM and 15 women without EM. PD-1/PD-L1 expression in endometrial tissues was detected using immunohistochemistry and western blot analysis. Their expression in blood was detected using flow cytometry. In addition, their expression was evaluated in endometrial cells after estrogen and cytokine treatment. We observed PD-1/PD-L1 expression in both eutopic and ectopic endometria, with elevated expression in EM. Their expression was also higher in CD4 + /CD8 + T cells in blood from EM patients. In addition, treatment with 17β-estradiol upregulated PD-L1 expression in eutopic epithelial cells in EM. These data suggest that the PD-1/PD-L1 pathway may be involved in EM immune dysfunction and be regulated by estrogen.

Background: Melatonin is a potential therapeutic agent for endometriosis, but its molecular mechanism is unclear. Here, we investigated the effect of melatonin on the epithelial-mesenchymal transition (EMT) in endometriotic endometrial epithelial cells and explored the pathway that might be involved., Methods: This hospital-based study included 60 women of reproductive age using the endometrium for immunohistochemistry, 6 women of reproductive age undergoing bilateral tubal ligation and 6 patients with endometriosis for isolation of endometrial epithelial cells or subsequent analysis, respectively. We examined the expression of Notch1/Numb signaling and EMT markers by immunohistochemistry analysis and western blot analysis, the invasion and migration of endometrial epithelial cells by transwell assays, and the cell proliferation by CCK8 assays., Results: Compared with normal endometrium, the endometriotic eutopic endometrium showed increased expression of Notch1, Slug, Snail, and N-cadherin, and decreased expression of E-cadherin and Numb. Melatonin or Notch inhibition by specific inhibitor blocked 17β-estradiol-induced cell proliferation, invasion, migration and EMT-related markers in both normal and endometriotic epithelial cells., Conclusions: Our data suggest that aberrant expression of Notch1/Numb signaling and the EMT is present in endometriotic endometrium. Melatonin may block 17β-estradiol-induced migration, invasion and EMT in normal and endometriotic epithelial cells by upregulating Numb expression and decreasing the activity of the Notch signaling pathway.

Stroma-tumor communication participates in the pathogenesis of endometrial carcinomas. In previous studies, we found that normal stromal cells inhibited the growth of endometrial carcinoma cells. Here, we investigated the role of normal stromal cells in the epithelial-mesenchymal transition (EMT) of endometrial carcinoma cells and explored the possible mechanism implied. We found that conditioned medium (CM) by normal endometrial stromal cells (NSC) reduced cell growth and induced cell apoptosis in Ishikawa cells. CM by NSC inhibited 17β-estradiol-induced cell growth and apoptosis decrease in Ishikawa cells. Moreover, CM by NSC inhibited the migration and invasion, and 17β-estradiol-induced migration and invasion in Ishikawa cells. Meanwhile, CM by NSC decreased Slug expression and 17β-estradiol-induced Slug expression, increased E-cadherin expression and abolished 17β-estradiol-induced E-cadherin reduction in Ishikawa cells. In conclusion, normal stromal factors can inhibit 17β-estradiol-induced cell proliferation and apoptosis inhibition, and abolished 17β-estradiol-induced EMT in endometrial cancer cell via regulating E-cadherin and Slug expression.

Phosphatase and tensin homolog (PTEN) and protein phosphatase type 2A (PP2A) are negative modulators of PI3K/AKT/survivin signaling. To evaluate immunoexpression of PTEN, PP2A and survivin in adenomyosis, ectopic lesions from 28 patients with adenomyosis and endometria from 30 controls without adenomyosis were employed in the study. The expression of PTEN, PP2A and survivin was examined with the use of immunohistochemistry. We found a decreased expression of PP2A and PTEN in adenomyosis. The expression of PTEN showed great individual differences in adenomyosis, although expression of both PP2A and PTEN was lower in adenomyosis than in normal endometria. In contrast, the expression of survivin was higher in adenomyosis. Our results suggest the important role of the PI3K cascade in the pathogenesis and development of adenomyosis., (Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Endometriosis is a common estrogen-dependent chronic inflammatory disease that leads to infertility in women of reproductive age. Perhaps infertility reflects the reduced expression of integrin αvβ3 and HOXA10 in endometriosis. Previous studies have shown that administration of letrozole, a non-steroidal aromatase inhibitor for cancer treatment, increased the clinical pregnancy rate in women with endometriosis, but the mechanisms remain to be determined. In this communication, a rat model of endometriosis was established. Animals were treated with letrozole at 2ug/kg of body weight, intragastric administration for 15 consecutive days. Letrozole increased the expression of αvβ3 and HOXA10 in the endometriosis model and endometrial receptivity. Abbreviations: WOI: window of implantation; RGD: Arg-Gly-Asp; HOX: homeobox; E2: estradiol; SPF: specific pathogen-free. [ABSTRACT FROM AUTHOR]

2Immunoexpression and comparison of B7-H3 in normal, eutopic and ectopic endometrium of adenomyosis treated with and without mifepristone. a Ectopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); b Ectopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); c Eutopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); d Eutopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); e Normal endometrium of proliferative phase in patients without adenomyosis (n = 47); f Normal endometrium of secretory phase in patients without adenomyosis (n = 27); g Ectopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); h and i eutopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); j Immunoscore comparation of B7-H3 between each groups, * P < 0.05, ** P < 0.01. a- i magnification: × 100 The original article [[1]] has been updated. Reference 1 Qin X, Sun W, Wang C. Mifepristone inhibited the expression of B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis. [Extracted from the article]

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Copyright of Gynecological Endocrinology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Previous studies report that fibroblast growth factor 2 (FGF2) modulates Sproutys (SPRYs)/dual specificity phosphatase 6 (DUSP6)/extracellular signal-regulated kinase (ERK) signaling pathway in endometrial glandular epithelial cells. However, its role in endometriosis remains unclear. The expression patterns and localization of related proteins in endometrium patients' samples were determined using quantitative reverse transcription PCR, Western blotting, and immunohistochemistry, respectively. Human endometrial stromal cells (HESCs) were isolated and transfected with small interfering RNA (siRNA) targeting FGF2 (FGF2-siRNA). Cell viability was determined using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. It was found that FGF2 mRNA and protein levels were increased in the ectopic endometrium, whilst the mRNA and protein levels of SPRYs/DUSP6/ERK signaling pathway related-genes were dysregulated. Spearman's rank correlation analysis revealed a negative correlation between FGF2 and SPRYs/DUSP6 signaling pathway-related proteins. In vitro study demonstrated that FGF2 silencing suppressed cell proliferation. Our results suggest that FGF2 upregulation might contribute to endometriosis via the regulation of the SPRYs/DUSP6/ERK signaling pathway. [ABSTRACT FROM AUTHOR]