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      Emodin Reverses the Epithelial–Mesenchymal Transition of Human Endometrial Stromal Cells by Inhibiting ILK/GSK-3β Pathway

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          Abstract

          Purpose

          To explore the exact mechanism through which emodin down-regulates the migration and invasion abilities of endometrial stromal cells. Moreover, to explore the theoretical basis of emodin in the treatment of endometriosis.

          Patients and Methods

          Endometriosis endometrial stromal cells (EESs) were cultured from 15 women with endometriosis and control endometrial stromal cells (CESs) were cultured from 12 women without endometriosis. The levels of proteins were evaluated by Western blot. The migration and invasion abilities of cells were detected by transwell assays.

          Results

          The abilities of migration and invasion of EESs were much stronger than those of CESs. After treated with emodin, the migration and invasion abilities of EESs and CESs were significantly down-regulated, and the levels of integrin-linked kinase (ILK) and p-GSK-3β were statistically down-regulated in EESs. Besides that, the expression of keratin was up-regulated while the expression of vimentin, β-catenin and slug were all down-regulated by emodin in a dose- and time-dependent manner. Silencing of ILK gene in EESs also achieved the above effects, which were strengthened by emodin. Conversely, exogenous expression of ILK in CESs increased the expression of p-GSK-3β, which were abrogated by emodin. Furthermore, SB216763 increased migration and invasion abilities of CESs by facilitating the epithelial–mesenchymal transition (EMT) through up-regulating levels of p-GSK-3β, β-catenin and slug, which were also abrogated by emodin.

          Conclusion

          Emodin inhibits the migration and invasion abilities of human endometrial stromal cells by reversing the EMT via ILK/GSK-3β pathway. So, emodin may be considered as a promising targeted therapy for endometriosis.

          Most cited references39

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          Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines.

          In mammalian cells, glycogen synthase kinase-3 (GSK-3) exists as two homologs, GSK-3alpha and GSK-3beta, encoded by independent genes, which share similar kinase domains but differ substantially in their termini. Here, we describe the generation of an allelic series of mouse embryonic stem cell (ESC) lines with 0-4 functional GSK-3 alleles and examine GSK-3-isoform function in Wnt/beta-catenin signaling. No compensatory upregulation in GSK-3 protein levels or activity was detected in cells lacking either GSK-3alpha or GSK-3beta, and Wnt/beta-catenin signaling was normal. Only in cells lacking three or all four of the alleles was a gene-dosage effect on beta-catenin/TCF-mediated transcription observed. Indeed, GSK-3alpha/beta double-knockout ESCs displayed hyperactivated Wnt/beta-catenin signaling and were severely compromised in their ability to differentiate, but could be rescued to normality by re-expression of functional GSK-3. The rheostatic regulation of GSK-3 highlights the importance of considering the contributions of both homologs when studying GSK-3 functions in mammalian systems.
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            Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression.

            Slug (Snail2) plays critical roles in regulating the epithelial-mesenchymal transition (EMT) programs operative during development and disease. However, the means by which Slug activity is controlled remain unclear. Herein we identify an unrecognized canonical Wnt/GSK3β/β-Trcp1 axis that controls Slug activity. In the absence of Wnt signaling, Slug is phosphorylated by GSK3β and subsequently undergoes β-Trcp1-dependent ubiquitination and proteosomal degradation. Alternatively, in the presence of canonical Wnt ligands, GSK3β kinase activity is inhibited, nuclear Slug levels increase, and EMT programs are initiated. Consistent with recent studies describing correlative associations in basal-like breast cancers between Wnt signaling, increased Slug levels, and reduced expression of the tumor suppressor Breast Cancer 1, Early Onset (BRCA1), further studies demonstrate that Slug-as well as Snail-directly represses BRCA1 expression by recruiting the chromatin-demethylase, LSD1, and binding to a series of E-boxes located within the BRCA1 promoter. Consonant with these findings, nuclear Slug and Snail expression are increased in association with BRCA1 repression in a cohort of triple-negative breast cancer patients. Together, these findings establish unique functional links between canonical Wnt signaling, Slug expression, EMT, and BRCA1 regulation.
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              • Abstract: found
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              ILK Expression in Colorectal Cancer Is Associated with EMT, Cancer Stem Cell Markers and Chemoresistance.

              Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) are critically implicated in cancer metastasis and chemoresistance. Herein, we investigated integrin-linked kinase (ILK)'s role in human colon cancer (CRC) progression and chemoresistance in relation to EMT and CSC markers.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                10 September 2020
                2020
                : 14
                : 3663-3672
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, Fujian Medical University , Fuzhou, Fujian 350001, People’s Republic of China
                Author notes
                Correspondence: Lihong Chen Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, Fujian Medical University , 20 Chazhong Road, Fuzhou, Fujian350001, People’s Republic of ChinaTel +86-059187982061Fax +86-059187981028 Email chenlihong_0102@126.com
                Article
                262816
                10.2147/DDDT.S262816
                7490435
                68401699-18ca-4b77-b093-2ba413e2a78c
                © 2020 Zheng et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 25 May 2020
                : 20 August 2020
                Page count
                Figures: 5, Tables: 1, References: 42, Pages: 10
                Funding
                Funded by: Fujian Medical University;
                Funded by: the Natural Science Foundation of Fujian Province;
                Funded by: the Joint Funds for the Innovation of Science and Technology, Fujian Province;
                This study was supported by grants from the Startup Fund for Scientific Research, Fujian Medical University (Grant number: 2017XQ1056), the Natural Science Foundation of Fujian Province (Grant number: 2018J05126), and the Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant number: 2018Y9077).
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                emodin,endometriosis,emt,ilk,gsk-3β
                Pharmacology & Pharmaceutical medicine
                emodin, endometriosis, emt, ilk, gsk-3β

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