Pathology & Oncology Research

, 15:533 | Cite as

Zonula Occludens-1, Occludin, and E-cadherin Protein Expression in Biliary Tract Cancers

  • Zsuzsanna Németh
  • Attila Marcell Szász
  • Áron Somorácz
  • Péter Tátrai
  • Júlia Németh
  • Hajnalka Győrffy
  • Attila Szíjártó
  • Péter Kupcsulik
  • András Kiss
  • Zsuzsa SchaffEmail author
Original Paper


The incidence of cholangiocarcinomas originating from intrahepatic and extrahepatic bile ducts, as well as of gallbladder carcinoma is increasing worldwide. The malignant transformation of biliary epithelia involves profound alterations of proteins in the intercellular junctions, among others zonula occludens-1 (ZO-1), occludin, and E-cadherin. Each plays important role in the maintenance of epithelial cell polarity and regulation of cell growth and differentiation. Our aim was to investigate ZO-1, occludin, and E-cadherin immunohistochemical reactions in tissue microarray blocks containing 57 normal and 62 neoplastic biliary tract samples. We demonstrated that the tight junction components ZO-1, occludin, and E-cadherin are downregulated in carcinomas arising from various compartments of the biliary tract (normal intrahepatic and extrahepatic bile ducts, gallbladder) as compared with their normal sites of origin. These results were confirmed by discriminant analysis yielding clear separation of the three normal sample groups from carcinomas in the corresponding locations.


Adherens junction Biliary tract cancer Tight junction 





gallbladder carcinomas


extrahepatic bile duct cancers


intrahepatic bile duct cancers


adherens junctions


tight junctions


zonula occludens-1


epithelial-to-mesenchymal transition


formalin-fixed, paraffin-embedded


Tissue Micro-Array


normal intrahepatic bile duct


normal extrahepatic bile duct


normal gall bladder



Authors wish to thank Mrs Magdolna Pekár and Mrs Erzsébet Azumah for preparing the TMAs and the immunohistochemical reactions and Mrs Elvira Kale-Rigo for the careful reading and correction of the manuscript.

This work was supported by Grant 75468 from the Hungarian Scientific Research Fund (OTKA).

Conflict of interest statement

The authors of the present study confirm that there is no conflict of interest to be declared.


  1. 1.
    Kakar S, Ferrell LD (2007) Tumors of the liver, gallbladder and biliary tree. In: Fletcher CDM (ed) Diagnostic histopathology of tumors, 3rd edn. Elsevier Limited, Philadelphia, pp 417–462Google Scholar
  2. 2.
    Chuang SC, Lee KT, Tsai KB, et al (2004) Immunohistochemical study of DPC4 and p53 proteins in gallbladder and bile duct cancers. World J Surg 28:995–1000CrossRefPubMedGoogle Scholar
  3. 3.
    Bajor J, Bero T, Garamszegi M, et al (2001) Common bile duct tumor in a young woman with ulcerative colitis. Orv Hetil 142:1231–1234PubMedGoogle Scholar
  4. 4.
    Hong SM, Kim MJ, Pi DY, et al (2005) Analysis of extrahepatic bile duct carcinomas according to the New American Joint Committee on Cancer staging system focused on tumor classification problems in 222 patients. Cancer 104:802–810CrossRefPubMedGoogle Scholar
  5. 5.
    Obama K, Ura K, Li M, et al (2005) Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma. Hepatology 41:1339–1348CrossRefPubMedGoogle Scholar
  6. 6.
    Lewis JT, Talwalkar JA, Rosen CB, et al (2007) Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol 31:907–913CrossRefPubMedGoogle Scholar
  7. 7.
    Kobayashi S, Ohnuma N, Yoshida H, et al (2006) Preferable operative age of choledochal dilation types to prevent patients with pancreaticobiliary maljunction from developing biliary tract carcinogenesis. Surgery 139:33–38CrossRefPubMedGoogle Scholar
  8. 8.
    Gonzalez-Mariscal L, Lechuga S, Garay E (2007) Role of tight junctions in cell proliferation and cancer. Prog Histochem Cytochem 42:1–57CrossRefPubMedGoogle Scholar
  9. 9.
    Hartsock A, Nelson WJ (2008) Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778(3):660–669CrossRefPubMedGoogle Scholar
  10. 10.
    Schneeberger EE, Lynch RD (2004) The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 286:C1213–C1228CrossRefPubMedGoogle Scholar
  11. 11.
    Rodriguez-Boulan E, Nelson WJ (1989) Morphogenesis of the polarized epithelial cell phenotype. Science 245:718–725CrossRefPubMedGoogle Scholar
  12. 12.
    Miyoshi J, Takai Y (2005) Molecular perspective on tight-junction assembly and epithelial polarity. Adv Drug Deliv Rev 57:815–855CrossRefPubMedGoogle Scholar
  13. 13.
    Gumbiner B (1987) Structure, biochemistry, and assembly of epithelial tight junctions. Am J Physiol 253:C749–C758PubMedGoogle Scholar
  14. 14.
    Gumbiner BM (1993) Breaking through the tight junction barrier. J Cell Biol 123:1631–1633CrossRefPubMedGoogle Scholar
  15. 15.
    Anderson JM, Van Itallie CM (1995) Tight junctions and the molecular basis for regulation of paracellular permeability. Am J Physiol 269:G467–G475PubMedGoogle Scholar
  16. 16.
    Ivanov AI, Nusrat A, Parkos CA (2005) Endocytosis of the apical junctional complex: mechanisms and possible roles in regulation of epithelial barriers. Bioessays 27:356–365CrossRefPubMedGoogle Scholar
  17. 17.
    Tsukita S, Furuse M, Itoh M (1999) Structural and signalling molecules come together at tight junctions. Curr Opin Cell Biol 11:628–633CrossRefPubMedGoogle Scholar
  18. 18.
    Balda MS, Matter K (1998) Tight junctions. J Cell Sci 111(Pt 5):541–547PubMedGoogle Scholar
  19. 19.
    Cowin P, Rowlands TM, Hatsell SJ (2005) Cadherins and catenins in breast cancer. Curr Opin Cell Biol 17:499–508CrossRefPubMedGoogle Scholar
  20. 20.
    Berx G, van Roy F (2001) The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res 3:289–293CrossRefPubMedGoogle Scholar
  21. 21.
    Guzman G, Chejfec G (2007) Tumors of the digestive system. In: Damjanov I, Fan F (ed) Cancer grading manual. Springer, New York, pp 43–44Google Scholar
  22. 22.
    Umeda K, Ikenouchi J, Katahira-Tayama S, et al (2006) ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell 126:741–754CrossRefPubMedGoogle Scholar
  23. 23.
    Hugh TJ, Dillon SA, Taylor BA, et al (1999) Cadherin-catenin expression in primary colorectal cancer: a survival analysis. Br J Cancer 80:1046–1051CrossRefPubMedGoogle Scholar
  24. 24.
    Truant SC, Gouyer VP, Leteurtre EA, et al (2008) E-Cadherin and beta-Catenin mRNA Levels Throughout Colon Cancer Progression. J Surg Res 2008 Feb 11 [Epub ahead of print]Google Scholar
  25. 25.
    Laurila JJ, Karttunen T, Koivukangas V, et al (2007) Tight junction proteins in gallbladder epithelium: different expression in acute acalculous and calculous cholecystitis. J Histochem Cytochem 55:567–573CrossRefPubMedGoogle Scholar
  26. 26.
    Kleeff J, Shi X, Bode HP, et al (2001) Altered expression and localization of the tight junction protein ZO-1 in primary and metastatic pancreatic cancer. Pancreas 23:259–265CrossRefPubMedGoogle Scholar
  27. 27.
    Medici D, Hay ED, Goodenough DA (2006) Cooperation between snail and LEF-1 transcription factors is essential for TGF-beta1-induced epithelial-mesenchymal transition. Mol Biol Cell 17:1871–1879CrossRefPubMedGoogle Scholar
  28. 28.
    Kurrey NK, K A, Bapat SA (2005) Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol Onco l97:155–165CrossRefPubMedGoogle Scholar
  29. 29.
    Ikenouchi J, Matsuda M, Furuse M, et al (2003) Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci 116:1959–1967CrossRefPubMedGoogle Scholar
  30. 30.
    Okada K, Shimura T, Asakawa K, et al (2007) Fascin expression is correlated with tumor progression of extrahepatic bile duct cancer. Hepatogastroenterology 54:17–21PubMedGoogle Scholar
  31. 31.
    Farazi PA, Zeisberg M, Glickman J, et al (2006) Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice. Cancer Res 66:6622–6627CrossRefPubMedGoogle Scholar
  32. 32.
    Hirata K, Ajiki T, Okazaki T, et al (2006) Frequent occurrence of abnormal E-cadherin/beta-catenin protein expression in advanced gallbladder cancers and its association with decreased apoptosis. Oncology 71:102–110PubMedGoogle Scholar
  33. 33.
    Settakorn J, Kaewpila N, Burns GF, et al (2005) FAT, E-cadherin, beta catenin, HER 2/neu, Ki67 immuno-expression, and histological grade in intrahepatic cholangiocarcinoma. J Clin Pathol 58:1249–1254CrossRefPubMedGoogle Scholar
  34. 34.
    Park S, Kim SW, Lee BL, et al (2006) Expression of E-cadherin and beta-catenin in the adenoma-carcinoma sequence of ampulla of Vater cancer. Hepatogastroenterology 53:28–32PubMedGoogle Scholar
  35. 35.
    Orban E, Szabo E, Lotz G, et al (2008) Different expression of Occludin and ZO-1 in primary and metastatic liver tumors. Pathol Oncol Res 14:299–306CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2009

Authors and Affiliations

  • Zsuzsanna Németh
    • 1
  • Attila Marcell Szász
    • 1
  • Áron Somorácz
    • 1
  • Péter Tátrai
    • 1
  • Júlia Németh
    • 1
  • Hajnalka Győrffy
    • 1
  • Attila Szíjártó
    • 2
  • Péter Kupcsulik
    • 2
  • András Kiss
    • 1
  • Zsuzsa Schaff
    • 1
    Email author
  1. 1.2nd Department of PathologySemmelweis UniversityBudapestHungary
  2. 2.1st Department of SurgerySemmelweis UniversityBudapestHungary

Personalised recommendations