Impaired Localization of Claudin-11 in Endometriotic Epithelial Cells Compared to Endometrial Cells

Claudins are the major components of tight junctions and are often deregulated in human cancer, permitting escape of cancer cells along with the acquisition of invasive properties. Similarly, endometrial cells also show invasive capabilities; however, the role of tight junctions in endometriosis has only rarely been examined. In this study, we analyzed the protein expression and localization of claudin-7 and claudin-11 in human eutopic and ectopic endometrium and endometrial cell lines. We identified claudin-7 primarily at the basolateral junctions of the glandular epithelial cells in eutopic endometrium as well as in the ectopic lesions in nearly all glands and cysts. Quantification of claudin-7 localization by HSCORE showed a slight increase in peritoneal and deep infiltrating endometriosis (DIE) compared to eutopic endometrium. In contrast, claudin-11 was localized mainly in the apicolateral junctions in nearly all glandular epithelial cells of the eutopic endometrium. Interestingly, we observed a deregulation of claudin-11 localization to a basal or basolateral localization in ovarian (P <.001), peritoneal (P <.01), and DIE (P <.05) and a moderately decreased abundance in ovarian endometriosis. In endometrial cell lines, claudin-7 was only present in epithelial Ishikawa cells, and silencing by small-interfering RNA increased cell invasiveness. In contrast, claudin-11 could be demonstrated in Ishikawa and endometriotic 12Z and 49Z cells. Silencing of claudin-11 decreased invasiveness of 12Z slightly but significantly in 49Z. We suggest that although claudin-7 and claudin-11 can be found in nearly all eutopic and ectopic epithelial cells, the impaired localization of claudin-11 in ectopic endometrium might contribute to the pathogenesis of endometriosis. Similar content being viewed by others

Clement PB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. 2007;14(4):241–260. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14(4):422–469. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68(4):585–595. Günzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93(2):525–569. Rosenthal R, Günzel D, Theune D, et al. Water channels and barriers formed by claudins. Ann N Y Acad Sci. 2017;1397(1):100–109. Singh AB, Uppada SB, Dhawan P. Claudin proteins, outside-in signaling, and carcinogenesis. Pflugers Arch. 2017;469(1):69–75. English DP, Santin AD. Claudins overexpression in ovarian cancer: potential targets for clostridium perfringens enterotoxin (CPE) based diagnosis and therapy. Int J Mol Sci. 2013;14(5):10412–10437. Li X, Li Y, Qiu H, Wang Y. Downregulation of claudin-7 potentiates cellular proliferation and invasion in endometrial cancer. Oncol Lett. 2013;6(1):101–105. Ding L, Lu Z, Foreman O, et al. Inflammation and disruption of the mucosal architecture in claudin-7-deficient mice. Gastroenterology. 2012;142(2):305–315. Dahiya N, Becker KG, Wood W, et al. Claudin-7 is frequently overexpressed in ovarian cancer and promotes invasion. Plos One. 2011;6(7):e22119. Morrow CM, Mruk D, Cheng CY, Hess RA. Claudin and occludin expression and function in the seminiferous epithelium. Philos Trans R Soc Lond B Biol Sci. 2010;365(1546):1679–1696. Yang J, Liu X, Yuan X, Wang Z. miR-99b promotes metastasis of hepatocellular carcinoma through inhibition of claudin 11 expression and may serve as a prognostic marker. Oncol Rep. 2015;34(3):1415–1423. Walesch SK, Richter AM, Helmbold P, Dammann RH. Claudin11 Promoter hypermethylation is frequent in malignant melanoma of the skin, but uncommon in nevus cell nevi. Cancers (Basel). 2015;7(3):1233–1243. Lin Z, Zhang X, Liu Q, et al. The distinct expression patterns of claudin-2, −6, and −11 between human gastric neoplasms and adjacent non-neoplastic tissues. Diagn Pathol. 2013;8:133. Nissinen L, Siljamäki E, Riihilä P, et al. Expression of claudin-11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ. Exp Dermatol. 2017;26(9):771–777. Gaetje R, Holtrich U, Engels K. Differential expression of claudins in human endometrium and endometriosis. Gynecol Endocrinol. 2008;24(8):442–449. Pan XY, Li X, Weng ZP, Wang B. Altered expression of claudin-3 and claudin-4 in ectopic endometrium of women with endometriosis. Fertil Steril. 2009;91(5):1692–1699. Schumann S, Buck VU, Classen-Linke I. Claudin-3, claudin-7, and claudin-10 show different distribution patterns during decidualization and trophoblast invasion in mouse and human. Histochem Cell Biol. 2015;144(6):571–585. Haas D, Chvatal R, Habelsberger A, et al. Comparison of revised american fertility society and ENZIAN staging: a critical evaluation of classifications of endometriosis on the basis of our patient population. Fertil Steril. 2011;95(5):1574–1578. Konrad L, Gronbach J, Horné F, et al. Similar characteristics of endometrial and endometriotic epithelial cells. Reprod Sci. 2019;26(1):49–59. Lee J, Banu SK, Rodriguez R, Starzinski-Powitz A, Arosh JA. Selective blockade of prostaglandin E2 receptors EP2 and EP4 signaling inhibits proliferation of human endometriotic epithelial cells and stromal cells through distinct cell cycle arrest. Fertil Steril. 2010;93(8):2498–2506. Zeitvogel A, Baumann R, Starzinski-Powitz A. Identification of an invasive, N-cadherin-expressing epithelial cell phenotype in endometriosis using a new cell culture model. Am J Pathol. 2001;159(5):1839–1852. Pollock K, Jaraczewski TJ, Carroll MJ, Lebovic DI, Kreeger PK. Endometriotic epithelial cell response to macrophage-secreted factors is dependent on extracellular matrix context. Cell Mol Bioeng. 2014;7(3):409–420. Correa LF, Zheng Y, Delaney AA, Khan Z, Shenoy CC, Daftary GS. TGF-β induces endometriotic progression via a noncanonical KLF11-mediated mechanism. Endocrinology. 2016;157(9):3332–3343. Cho S, Mutlu L, Zhou Y, Taylor HS. Aromatase inhibitor regulates let-7 expression and let-7f-induced cell migration in endometrial cells from women with endometriosis. Fertil Steril. 2016;106(3):673–680. Singh M, Spoelstra NS, Jean A, et al. ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol. 2008;21(7):912–923. Stammler A, Lüftner BU, Kliesch S, et al. Highly conserved testicular localization of claudin-11 in normal and impaired spermatogenesis. Plos One. 2016;11(8):e0160349. Thompson EW, Newgreen DF. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?. Cancer Res. 2005;65(14):5991–5995. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell 2017;168(4):670–691. Agarwal R, D’Souza T, Morin PJ. Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res. 2005;65(16):7378–7385. De Wever O, Pauwels P, De Craene B, et al. Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol. 2008;130(3):481–494. Bilyk O, Coatham M, Jewer M, Postovit LM. Epithelial-to-mesenchymal transition in the female reproductive tract: from normal functioning to disease pathology. Front Oncol. 2017;7:145. Fink C, Weigel R, Fink L, et al. Claudin-11 is over-expressed and dislocated from the blood-testis barrier in Sertoli cells associated with testicular intraepithelial neoplasia in men. Histochem Cell Biol. 2009;131(6):755–764. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Horné, F., Dietze, R., Berkes, E. et al. Impaired Localization of Claudin-11 in Endometriotic Epithelial Cells Compared to Endometrial Cells. Reprod. Sci. 26, 1181–1192 (2019). https://doi.org/10.1177/1933719118811643 Published: Version of record: Issue date: DOI: https://doi.org/10.1177/1933719118811643