Emodin Inhibits Migration and Invasion of Human Endometrial Stromal Cells by Facilitating the Mesenchymal–Epithelial Transition Through Targeting ILK

Objective To determine whether emodin facilitates the mesenchymal–epithelial transition (MET) of endometrial stromal cells (ESCs) as well as to explore the mechanism through which emodin favored the MET of ESCs.

Cell viability was tested by methyl thiazolyl tetrazolium assay. Cell migration and invasion abilities were detected by transwell assays. Levels of integrin-linked kinase (ILK) and epithelial–mesenchymal transition (EMT)-related proteins were detected by Western blot.

Upregulated ILK and increased abilities of migration and invasion were confirmed in the eutopic and ectopic ESCs (EuSCs and EcSCs), especially in the EcSCs. After treated with emodin, the expression of ILK was statistically downregulated in EcSCs, resulting in the MET and decreased migration and invasion abilities of EcSCs. Additionally, silencing of the ILK gene in EcSCs also achieved the above-mentioned effects, which were strengthened by emodin. Furthermore, exogenous expression of ILK in control ESCs (CSCs) resulted in the EMT and increased abilities of migration and invasion of CSCs, which can be abrogated by emodin. Besides, exogenous expression of ILK also abrogated the effects of emodin on CSCs.

Emodin inhibits the migration and invasion abilities of human ESCs by facilitating the MET through targeting ILK. Similar content being viewed by others Change history 01 June 2022 A Correction to this paper has been published: https://doi.org/10.1007/s43032-022-00984-1

Culley L, Law C, Hudson N, et al. The social and psychological impact of endometriosis on women’s lives: a critical narrative review. Hum Reprod Update. 2013;19(6):625–639. Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):177–200. Duffy JM, Arambage K, Correa FJ, et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014;No. 4:CD011031. Tanprasertkul C, Patumanond J, Manusook S, et al. Recurrence of endometrioma following conservative ovarian endometrioma cystectomy: laparoscopy versus laparotomy. J Med Assoc Thai. 2015;98(suppl 3):S96–S100. Sampson J. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;3(2):422–469. Proestling K, Birner P, Gamperl S, et al. Enhanced epithelial to mesenchymal transition (EMT) and upregulated MYC in ectopic lesions contribute independently to endometriosis. Reprod Biol Endocrinol. 2015;13:75. Matsuzaki S, Darcha C. Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. Hum Reprod. 2012;27(3):712–721. Bartley J, Julicher A, Hotz B, Mechsner S, Hotz H. Epithelial to mesenchymal transition (EMT) seems to be regulated differently in endometriosis and the endometrium. Arch Gynecol Obstet. 2014;289(4):871–881. Wu C, Dedhar S. Integrin-linked kinase (ILK) and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes. J Cell Biol. 2001;155(4):505–510. Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005;5(1):51–63. Mcdonald PC, Fielding AB, Dedhar S. Integrin-linked kinase–essential roles in physiology and cancer biology. J Cell Sci. 2008;121(pt 19):3121–3132. Chou CC, Chuang HC, Salunke SB, Kulp SK, Chen CS. A novel HIF-1alpha-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1alpha expression and epithelial–mesenchymal transition in cancer cells. Oncotarget. 2015;6(10):8271–8285. Yan Z, Yin H, Wang R, et al. Overexpression of integrin-linked kinase (ILK) promotes migration and invasion of colorectal cancer cells by inducing epithelial–mesenchymal transition via NF-kappaB signaling. Acta Histochem. 2014;116(3):527–533. Tan C, Costello P, Sanghera J, et al. Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC−/− human colon carcinoma cells. Oncogene. 2001;20(1):133–140. Demirezer LO, Kuruuzum-Uz A, Bergere I, Schiewe HJ, Zeeck A. The structures of antioxidant and cytotoxic agents from natural source: anthraquinones and tannins from roots of Rumex patientia. Phytochemistry. 2001;58(8):1213–1217. Wang HH, Chung JG. Emodin-induced inhibition of growth and DNA damage in the Helicobacter pylori. Curr Microbiol. 1997;35(5):262–266. Chang CH, Lin CC, Yang JJ, Namba T, Hattori M. Anti-inflammatory effects of emodin from Ventilago leiocarpa. Am J Chin Med. 1996;24(2):139–142. Huang HC, Chang JH, Tung SF, Wu RT, Foegh ML, Chu SH. Immunosuppressive effect of emodin, a free radical generator. Eur J Pharmacol. 1992;211(3):359–364. Jing X, Ueki N, Cheng J, Imanishi H, Hada T. Induction of apoptosis in hepatocellular carcinoma cell lines by emodin. Jpn J Cancer Res. 2002;93(8):874–882. Chen T, Zheng LY, Xiao W, Gui D, Wang X, Wang N. Emodin ameliorates high glucose induced-podocyte epithelial–mesenchymal transition in-vitro and in-vivo. Cell Physiol Biochem. 2015;35(4):1425–1436. Chan TC, Chang CJ, Koonchanok NM, Geahlen RL. Selective inhibition of the growth of ras-transformed human bronchial epithelial cells by emodin, a protein–tyrosine kinase inhibitor. Biochem Biophys Res Commun. 1993;193(3):1152–1158. Shi YQ, Fukai T, Sakagami H, et al. Cytotoxic and DNA damage-inducing activities of low molecular weight phenols from rhubarb. Anticancer Res. 2001;21(4A):2847–2853. Xu X, Zheng Q, Zhang Z, Zhang X, Liu R, Liu P. Periostin enhances migration, invasion, and adhesion of human endometrial stromal cells through integrin-linked kinase 1/Akt signaling pathway. Reprod Sci. 2015;22(9):1098–1106. Qian Y, Zhong X, Flynn DC, et al. ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling. Oncogene. 2005;24(19):3154–3165. Lin SW, Ke FC, Hsiao PW, Lee PP, Lee MT, Hwang JJ. Critical involvement of ILK in TGFbeta1-stimulated invasion/migration of human ovarian cancer cells is associated with urokinase plasminogen activator system. Exp Cell Res. 2007;313(3):602–613. Wong RP, Ng P, Dedhar S, Li G. The role of integrin-linked kinase in melanoma cell migration, invasion, and tumor growth. Mol Cancer Ther. 2007;6(6):1692–1700. Chen D, Zhang Y, Zhang X, et al. Overexpression of integrin-linked kinase correlates with malignant phenotype in non-small cell lung cancer and promotes lung cancer cell invasion and migration via regulating epithelial–mesenchymal transition (EMT)-related genes. Acta Histochem. 2013;115(2):128–136. Han KS, Li N, Raven PA, et al. Targeting integrin-linked kinase suppresses invasion and metastasis through downregulation of epithelial-to-mesenchymal transition in renal cell carcinoma. Mol Cancer Ther. 2015;14(4):1024–1034. Ok S, Kim SM, Kim C, et al. Emodin inhibits invasion and migration of prostate and lung cancer cells by downregulating the expression of chemokine receptor CXCR4. Immunopharmacol Immunotoxicol. 2012;34(5):768–778. Manu KA, Shanmugam MK, Ong TH, et al. Emodin suppresses migration and invasion through the modulation of CXCR4 expression in an orthotopic model of human hepatocellular carcinoma. PLoS One. 2013;8(3):e57015. Sun Y, Wang X, Zhou Q, et al. Inhibitory effect of emodin on migration, invasion and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo. Oncol Rep. 2015;33(1):338–346. Zou J, Luo H, Zeng Q, Dong Z, Wu D, Liu L. Protein kinase CK2alpha is overexpressed in colorectal cancer and modulates cell proliferation and invasion via regulating EMT-related genes. J Transl Med. 2011;9:97. Way TD, Huang JT, Chou CH, Huang CH, Yang MH, Ho CT. Emodin represses TWIST1-induced epithelial–mesenchymal transitions in head and neck squamous cell carcinoma cells by inhibiting the beta-catenin and Akt pathways. Eur J Cancer. 2014;50(2):366–378. Tang Q, Zhao S, Wu J, et al. Inhibition of integrin-linked kinase expression by emodin through crosstalk of AMPKalpha and ERK1/2 signaling and reciprocal interplay of Sp1 and c-Jun. Cell Signal. 2015;27(7):1469–1477. Liu H, Gu LB, Tu Y, Hu H, Huang YR, Sun W. Emodin ameliorates cisplatin-induced apoptosis of rat renal tubular cells in vitro by activating autophagy. Acta Pharmacol Sin. 2016;37(2):235–245. Chen Z, Zhang L, Yi J, Yang Z, Zhang Z, Li Z. Promotion of adiponectin multimerization by emodin: a novel AMPK activator with PPARgamma-agonist activity. J Cell Biochem. 2012;113(11):3547–3558. Lu Y, Jeong YT, Li X, et al. Emodin isolated from Polygoni cuspidati radix inhibits TNF-alpha and IL-6 release by blockading NF-kappaB and MAP kinase pathways in mast cells stimulated with PMA Plus A23187. Biomol Ther (Seoul). 2013;21(6):435–441. Jabor Gozzi G, Bouaziz Z, Winter E, et al. Converting potent indeno[1,2-b]indole inhibitors of protein kinase CK2 into selective inhibitors of the breast cancer resistance protein ABCG2. J Med Chem. 2015;58(1):265–277. Han YM, Lee SK, Jeong DG, et al. Emodin inhibits migration and invasion of DLD-1 (PRL-3) cells via inhibition of PRL-3 phosphatase activity. Bioorg Med Chem Lett. 2012;22(1):323–326. Feng Y, Huang SL, Dou W, et al. Emodin, a natural product, selectively inhibits 11beta-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice. Br J Pharmacol. 2010;161(1):113–126. Taylor HS, Osteen KG, Bruner-Tran KL, et al. Novel therapies targeting endometriosis. Reprod Sci. 2011;18(9):814–823. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Zheng, Q., Xu, Y., Lu, J. et al. Emodin Inhibits Migration and Invasion of Human Endometrial Stromal Cells by Facilitating the Mesenchymal–Epithelial Transition Through Targeting ILK. Reprod. Sci. 23, 1526–1535 (2016). https://doi.org/10.1177/1933719116645192 Published: Issue date: DOI: https://doi.org/10.1177/1933719116645192