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EpCAM is decreased but is still present in uterine epithelial cells during early pregnancy in the rat: potential mechanism for maintenance of mucosal integrity during implantation

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Abstract

The non-receptive uterine luminal epithelium forms a polarised epithelial barrier, protective against potential pathogenic assault from the external environment and invasion by the blastocyst. However, during the window of implantation, the uterine luminal epithelial cells (UECs) transition to a receptive state by dismantling many of their intercellular and cell–matrix adhesions in preparation for epithelial detachment and subsequent blastocyst implantation. The present study investigated the presence and regulation of the intercellular adhesion protein, Epithelial Cell Adhesion Molecule (EpCAM) during early pregnancy in the rat to understand its role in the transition to receptivity. Immunofluorescence and western blotting analysis were used to study EpCAM expression in normal pregnancy, hormone replacement studies and pseudopregnancy. EpCAM was abundantly expressed and localised to the uterine luminal and glandular epithelium during the non-receptive state but decreased to lower but still observable levels around the time of implantation. This decrease was not dependent on ovarian hormones or the blastocyst. Further, EpCAM colocalised with but did not associate with its frequent binding partner, Tumour necrosis factor α (TNFα)-converting enzyme, also known as A Disintegrin And Metalloprotease 17 (TACE/ADAM17), at the time of fertilisation. These results suggest that, prior to implantation, EpCAM mediates intercellular adhesion in the uterine epithelium, but that, during implantation when UECs lose the majority of their intercellular and cell–matrix adhesions, EpCAM levels are decreased but still present for the maintenance of mucosal integrity.

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References

  • Abrahamsohn P, Zorn T (1993) Implantation and decidualization in rodents. J Exp Zool 266:603–628

    Article  CAS  PubMed  Google Scholar 

  • Aplin JD, Kimber SJ (2004) Trophoblast-uterine interactions at implantation. Reprod Biol Endocrinol 2:48–48

    Article  PubMed Central  PubMed  Google Scholar 

  • Balzar M, Bakker HA, Briaire-de-Bruijn IH et al (1998) Cytoplasmic tail regulates the intercellular adhesion function of the epithelial cell adhesion molecule. Mol Cell Biol 18:4833–4843

    CAS  PubMed Central  PubMed  Google Scholar 

  • Balzar M, Winter MJ, de Boer CJ, Litvinov SV (1999) The biology of the 17-1A antigen (Ep-CAM). J Mol Med Berl 77:699–712

    Article  CAS  PubMed  Google Scholar 

  • Cirulli VV, Crisa LL, Beattie GMG et al (1998) KSA antigen Ep-CAM mediates cell-cell adhesion of pancreatic epithelial cells: morphoregulatory roles in pancreatic islet development. J Cell Biol 140:1519–1534

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • de Boer CJ, van Krieken JH, Janssen-van Rhijn CM, Litvinov SV (1999) Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver. J Pathol 188:201–206

    Article  PubMed  Google Scholar 

  • Denker H-W (1993) Endometrial receptivity: cell biological aspects of an unusual epithelium. A review. Ann Anat 176:53–60

    Article  Google Scholar 

  • Denzel S, Maetzel D, Mack B et al (2008) Initial activation of EpCAM cleavage via cell-to-cell contact. BMC Cancer 9:402–402

    Article  Google Scholar 

  • Denzel S, Mack B, Eggert C et al (2012) MMP7 is a target of the tumour-associated antigen EpCAM. Int J Exp Pathol 93:341–353

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Driemel C, Kremling H, Schumacher S et al (2013) Context-dependent adaption of EpCAM expression in early systemic esophageal cancer. Oncogene. doi:10.1038/onc.2013.441

    PubMed  Google Scholar 

  • Frederick BA, Helfrich BA, Coldren CD et al (2007) Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther 6:1683–1691

    Article  CAS  PubMed  Google Scholar 

  • Gadalla S-E, Ojemalm K, Vasquez PL et al (2013) EpCAM associates with endoplasmic reticulum aminopeptidase 2 (ERAP2) in breast cancer cells. Biochem Biophys Res Commun 439:203–208

    Article  CAS  PubMed  Google Scholar 

  • Gires O (2012) EpCAM in hepatocytes and their progenitors. J Hepatol 56:490–492

    Article  CAS  PubMed  Google Scholar 

  • Goulet OO, Salomon JJ, Ruemmele FF et al (2006) Intestinal epithelial dysplasia (tufting enteropathy). Orphanet J Rare Dis 2:20–20

    Article  Google Scholar 

  • Groothuis PG, Dassen HHNM, Romano A, Punyadeera C (2007) Estrogen and the endometrium: lessons learned from gene expression profiling in rodents and human. Hum Reprod Update 13:405–417

    Article  CAS  PubMed  Google Scholar 

  • Hussenet F, Dousset B, Cordonnier JL et al (1993) Tumour necrosis factor alpha and interleukin 2 in normal and infected human seminal fluid. Hum Reprod 8:409–411

    CAS  PubMed  Google Scholar 

  • Kaneko YY, Lindsay LAL, Murphy CRC (2008) Focal adhesions disassemble during early pregnancy in rat uterine epithelial cells. Reprod Fertil Dev 20:892–899

    Article  CAS  PubMed  Google Scholar 

  • Kaneko Y, Lecce L, Day ML, Murphy CR (2011) β1 and β3 integrins disassemble from basal focal adhesions and β3 integrin is later localised to the apical plasma membrane of rat uterine luminal epithelial cells at the time of implantation. Reprod Fertil Dev 23:481–495

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Kang SG, Kim JI et al (2006) Implication of ADAM-8, −9, −10, −12, −15, −17, and ADAMTS-1 in implantational remodeling of a mouse uterus. Yonsei Med J 47:558–567

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ladwein M, Pape U-F, Schmidt D-S et al (2005) The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7. Exp Cell Res 309:345–357

    Article  CAS  PubMed  Google Scholar 

  • Le Naour F, Zöller M (2008) The tumor antigen EpCAM: tetraspanins and the tight junction protein claudin-7, new partners, new functions. Front Biosci 13:5847–5865. doi:10.2741/3121

    Article  PubMed  Google Scholar 

  • Lei Z, Maeda T, Tamura A et al (2012) EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins. Dev Biol 371:136–145

    Article  CAS  PubMed  Google Scholar 

  • Litvinov SV, Velders MP, Bakker HA et al (1994) Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 125:437–446

    Article  CAS  PubMed  Google Scholar 

  • Ljungkvist I (1971a) Attachment reaction of rat uterine luminal epithelium. II. The effect of progesterone on the morphology of the uterine glands and the luminal epithelium of the spayed, virgin rat. Acta Soc Med Ups 76:110–126

    CAS  PubMed  Google Scholar 

  • Ljungkvist I (1971b) Attachment reaction of rat uterine luminal epithelium. 3. The effect of estradiol, estrone and estriol on the morphology of the luminal epithelium of the spayed, virgin rat. Acta Soc Med Ups 76:139–157

    CAS  PubMed  Google Scholar 

  • Long JA and Evans HM (1922) The oestrous cycle in the rat and its associated phenomena. Memoirs of University of California 6:1–148

  • Lu DPD, Tian LL, O’Neill CC, King NJCN (2002) Regulation of cellular adhesion molecule expression in murine oocytes, peri-implantation and post-implantation embryos. Cell Res 12:373–383

    Article  PubMed  Google Scholar 

  • Maetzel D, Denzel S, Mack B et al (2009) Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 11:162–171

    Article  CAS  PubMed  Google Scholar 

  • Maretzky T, Scholz F, Köten B et al (2008) ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis. J Invest Dermatol 128:1737–1746

    Article  CAS  PubMed  Google Scholar 

  • Mueller JL, McGeough MD, Pena CA, Sivagnanam M (2014) Functional consequences of EpCAM mutation in mice and men. Am J Physiol Gastrointest Liver Physiol 306:G278–G288

    Article  CAS  PubMed  Google Scholar 

  • Munz M, Kieu C, Mack B et al (2004) The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23:5748–5758

    Article  PubMed  Google Scholar 

  • Munz M, Zeidler R, Gires O (2005) The tumour-associated antigen EpCAM upregulates the fatty acid binding protein E-FABP. Cancer Lett 225:151–157

    Article  PubMed  Google Scholar 

  • Murphy CR (2004) Uterine receptivity and the plasma membrane transformation. Cell Res 14:259–267

    Article  PubMed  Google Scholar 

  • Nicholson MDO, Lindsay LA, Murphy CR (2010) Ovarian hormones control the changing expression of claudins and occludin in rat uterine epithelial cells during early pregnancy. Acta Histochem 112:42–52

    Article  CAS  PubMed  Google Scholar 

  • Osta WA, Chen Y, Mikhitarian K et al (2004) EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res 64:5818–5824

    Article  CAS  PubMed  Google Scholar 

  • Poon CE, Madawala RJ, Day ML, Murphy CR (2013) Claudin 7 is reduced in uterine epithelial cells during early pregnancy in the rat. Histochem Cell Biol 139:583–593

    Article  CAS  PubMed  Google Scholar 

  • Schmidt D-SD, Klingbeil PP, Schnölzer MM, Zöller MM (2004) CD44 variant isoforms associate with tetraspanins and EpCAM. Exp Cell Res 297:329–347

    Article  CAS  PubMed  Google Scholar 

  • Schnell U, Kuipers J, Giepmans BNG (2013) EpCAM proteolysis: new fragments with distinct functions? Biosci Rep 33:e00030. doi:10.1042/BSR20120128

    Article  PubMed Central  PubMed  Google Scholar 

  • Sharkey DJ, Tremellen KP, Jasper MJ et al (2012) Seminal fluid induces leukocyte recruitment and cytokine and chemokine mRNA expression in the human cervix after coitus. J Immunol 188:2445–2454. doi:10.4049/jimmunol.1102736

    Article  CAS  PubMed  Google Scholar 

  • Sivagnanam M, Mueller JL, Lee H et al (2008) Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology 135:429–437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Trzpis MM, McLaughlin PMJP, de Lou MFHLM, Leij HMCM (2007) Epithelial cell adhesion molecule: more than a carcinoma marker and adhesion molecule. Am J Pathol 171:386–395

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wira CR, Grant-Tschudy KS, Crane-Godreau MA (2005) Epithelial cells in the female reproductive tract: a central role as sentinels of immune protection. Am J Reprod Immunol 53:65–76

    Article  CAS  PubMed  Google Scholar 

  • Wu C-J, Mannan P, Lu M, Udey MC (2013) Epithelial cell adhesion molecule (EpCAM) regulates claudin dynamics and tight junctions. J Biol Chem 288:12253–12268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yoon S-M, Gerasimidou D, Kuwahara R et al (2011) Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Hepatology 53:964–973

    Article  PubMed  Google Scholar 

  • Yoshinaga K (1987) Uterine receptivity for blastocyst implantation. Ann NY Acad Sci 541:424–431

    Article  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Dr Laura A. Lindsay and Mr Samson Dowland for assistance with manuscript editing, Dr Louise Cole (Core Facilities Manager, Bosch Institute Advanced Microscopy Facility, The University of Sydney) for her assistance with the microscopy imaging (Zeiss Deconvolution and Zeiss LSM 510 Metaconfocal microscopes) and Dr Donna Lai (Molecular Biology Officer, Bosch Institute Molecular Biology Facility, The University of Sydney) for her support with western blotting.

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Correspondence to Connie E. Poon.

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Poon, C.E., Madawala, R.J., Day, M.L. et al. EpCAM is decreased but is still present in uterine epithelial cells during early pregnancy in the rat: potential mechanism for maintenance of mucosal integrity during implantation. Cell Tissue Res 359, 655–664 (2015). https://doi.org/10.1007/s00441-014-2017-3

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  • DOI: https://doi.org/10.1007/s00441-014-2017-3

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