Skip to main content

Advertisement

SpringerLink
Log in

Expression of APC, β-catenin and E-cadherin in Tunisian patients with gastric adenocarcinoma: clinical significance

  • Research Article
  • Published:
Tumor Biology

Abstract

Aberrant activation of the Wnt signalling pathway is a key feature of many cancers. β-Catenin, adenomatous polyposis coli (APC) and E-cadherin are major players in this pathway. The aim of this study is to examine the expression of β-catenin, APC and E-cadherin in tumour tissues of 80 Tunisian patients with gastric carcinoma and to determine the methylation status of the APC promoter in tumour tissues. Associations between protein expression and clinico-pathological parameters, including prognosis, were performed. Positive expression of β-catenin, APC and E-cadherin was observed in 77.5, 68.7 and 60 % of cases, respectively. Tumours lacking membranous expression of β-catenin had greater extent of lymph node metastasis, poor differentiation and advanced T-stage. The expression of E-cadherin correlated with poor differentiation (P = 0.05) and β-catenin expression (P = 0.004). With regards to prognosis, the overall survival time was significantly prolonged for patients showing normal β-catenin expression (exclusively or predominantly membranous staining) alone or combined with positive APC expression (P log rank = 0.008 and 0.003, respectively). The methylated pattern of APC promoter 1A was detected in 43.8 % of cases and correlated with T-stage (P = 0.046) and distant metastasis (P = 0.037). No correlation was found between the methylated profile of APC promoter 1A and the expression of APC protein in tumour tissues. Our findings suggest that deregulation of the Wnt pathway via abnormal expression of β-catenin and E-cadherin occurred frequently in gastric carcinoma and correlated with worse clinical behaviour.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Parkin D, Bray F, Ferlay J, Pisani P. Global cancer statistics. CA Cancer J Clin. 2002;55:74–108.

    Article  Google Scholar 

  2. Jang BG, Kim WH. Molecular pathology of gastric carcinoma. Pathobiology. 2011;78:302–10.

    Article  PubMed  CAS  Google Scholar 

  3. Gumbiner BM. Signal transduction by b-catenin. Curr Opin Cell Biol. 1995;7:634–40.

    Article  PubMed  CAS  Google Scholar 

  4. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 2004;303:1483–7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.

    PubMed  CAS  Google Scholar 

  6. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387–98.

    Article  PubMed  CAS  Google Scholar 

  7. Jamora C, Fuchs E. Intercellular adhesion, signalling and the cytoskeleton. Nat Cell Biol. 2002;4:101–8.

    Article  CAS  Google Scholar 

  8. Ohene-Abuakwa Y, Noda M, Perenyi M, Kobayashi N, Kashima K, Hattori T, et al. Expression of the E-cadherin/catenin (alpha-, beta-, and gamma-) complex correlates with the macroscopic appearance of early gastric cancer. J Pathol. 2000;192:433–9.

    Article  PubMed  CAS  Google Scholar 

  9. Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C, et al. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 2002;62:3503–6.

    PubMed  CAS  Google Scholar 

  10. Udhayakumar G, Jayanthi V, Devaraj N, Devaraj H. Nuclear translocation of β-catenin correlates with CD44 upregulation in Helicobacter pylori-infected gastric carcinoma. Mol Cell Biochem. 2011;357:283–93.

    Article  PubMed  CAS  Google Scholar 

  11. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/β-catenin/TCF pathway in colorectal cancer. Cancer Res. 1998;58:1130–4.

    PubMed  CAS  Google Scholar 

  12. Ebert MP, Fei G, Kahmann S, Müller O, Yu J, Sung JJ, et al. Increased beta-catenin mRNA levels and mutational alterations of the APC and beta-catenin gene are present in intestinal-type gastric cancer. Carcinogenesis. 2002;23:87–91.

    Article  PubMed  CAS  Google Scholar 

  13. Tamura G, Maesawa C, Suzuki Y, Tamada H, Satoh M, Ogasawara S, et al. Mutations of the APC gene occur during early stages of gastric adenoma development. Cancer Res. 1994;54:1149–51.

    PubMed  CAS  Google Scholar 

  14. Endoh Y, Sakata K, Tamura G, Ohmura K, Ajioka Y, Watanabe H, et al. Cellular phenotypes of differentiated-type adenocarcinomas and precancerous lesions of the stomach are dependent on the genetic pathways. J Pathol. 2000;191:257–63.

    Article  PubMed  CAS  Google Scholar 

  15. Jeeyun L, van Hummelen P, Go C, Palescandolo E, Jang J, Park HY, et al. High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma. Plos One. 2012;7(6).

  16. Tsuchiya T, Tamura G, Sato K, Endoh Y, Sakata K, Jin Z, et al. Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia. Oncogene. 2000;27:3642–6.

    Article  CAS  Google Scholar 

  17. Kang GH, Lee S, Kim JS, Jung HY. Profile of aberrant CpG island methylation along multistep gastric carcinogenesis. Lab Invest. 2003;83:519–26.

    Article  PubMed  CAS  Google Scholar 

  18. Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol. 1998;153:333–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Gumbiner BM. Regulation of cadherin adhesive activity. J Cell Biol. 2000;148:399–404.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Hashimoto M, Niwa O, Nitta Y, Takeichi M, Yokoro K. Unstable expression of E-cadherin adhesion molecules in metastatic ovarian tumor cells. Jpn Cancer Res. 1989;80:459–63.

    Article  CAS  Google Scholar 

  21. El-Bahrawy MA, Poulsom R, Jeffery R, Talbot I, Alison MR. The expression of E-cadherin and catenins in sporadic colorectal carcinoma. Hum Pathol. 2001;32:1216–24.

    Article  PubMed  CAS  Google Scholar 

  22. Cobanoglu U, Ersoz S, Turgutalp H, Reis A, Ozoran Y. Correlation of E-cadherin expression with clinicopathological parameters in breast carcinoma. Saudi Med J. 2004;25:1024–7.

    PubMed  Google Scholar 

  23. Graziano F, Arduini F, Ruzzo A, Mandolesi A, Bearzi I, Silva R, et al. Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer: implications for treatment with demethylating drugs. Ann Oncol. 2004;15:489–92.

    Article  PubMed  CAS  Google Scholar 

  24. Wang L, Zhang F, Wu PP, Jiang XC, Zheng L, Yu YY. Disordered beta-catenin expression and E-cadherin/CDH1 promoter methylation in gastric carcinoma. World J Gastroenterol. 2006;12:4228–31.

    PubMed  CAS  Google Scholar 

  25. Berx G, Becker KF, Hofler H, van Roy F. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat. 1998;12:226–37.

    Article  PubMed  CAS  Google Scholar 

  26. Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004;41:508–17.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Castro Alves C, Carneiro F, Hoefler H, Becker KF. Role of the epithelial–mesenchymal transition regulator Slug in primary human cancers. Front Biosci. 2009;14:3035–50.

    Article  Google Scholar 

  28. Carvalho J, van Grieken NC, Pereira PM, Sousa S, Tijssen M, Buffart TE, et al. Lack of microRNA-101 causes E-cadherin functional deregulation through EZH2 upregulation in intestinal gastric cancer. J Pathol. 2012;228:31–44.

    PubMed  CAS  Google Scholar 

  29. Kurashige J, Kamohara H, Watanabe M, Hiyoshi Y, Iwatsuki M, Tanaka Y, et al. MicroRNA-200b regulates cell proliferation, invasion, and migration by directly targeting ZEB2 in gastric carcinoma. Ann Surg Oncol. 2012;19:656–64.

    Article  Google Scholar 

  30. Sobin LH, Fleming ID. TNM classification of malignant tumors, fifth edition. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4.

    Article  PubMed  CAS  Google Scholar 

  31. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR. A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996;93:9821–6.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Karray-Chouayekh S, Trifa F, Khabir A, Boujelbene N, Sellami-Boudawara T, Daoud J, et al. Methylation status and overexpression of COX-2 in Tunisian patients with ductal invasive breast carcinoma. Tumor Biol. 2011;32:461–8.

    Article  CAS  Google Scholar 

  33. BenAyed-Guerfali D, Ayadi W, Miladi-Abdennadher I, Khabir A, Sellami-Boudawara T, Gargouri A, et al. Characteristics of Epstein Barr virus variants associated with gastric carcinoma in Southern Tunisia. Virol J. 2011;8:500. doi:10.1186/1743-422X-8-500.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Jawhari A, Jordan S, Poole S, Browne P, Pignatelli M, Farthing MJ. Abnormal immunoreactivity of the E-cadherin–catenin complex in gastric carcinoma: relationship with patient survival. Gastroenterology. 1997;112:46–54.

    Article  PubMed  CAS  Google Scholar 

  35. Grabsch H, Takeno S, Noguchi T, Hommel G, Gabbert HE, Mueller W. Different patterns of beta-catenin expression in gastric carcinomas: relationship with clinicopathological parameters and prognostic outcome. Histopathology. 2001;39:141–9.

    Article  PubMed  CAS  Google Scholar 

  36. Zhou YN, Xu CP, Han B, Li M, Qiao L, Fang DC, et al. Expression of E-cadherin and b-catenin in gastric carcinoma and its correlation with the clinicopathological features and patient survival. World J Gastroenterol. 2002;8:987–93.

    PubMed  CAS  Google Scholar 

  37. Retterspitz MF, Mönig SP, Schreckenberg S, Schneider PM, Hölscher AH, Dienes HP, et al. Expression of {beta}-catenin, MUC1 and c-met in diffuse-type gastric carcinomas: correlations with tumour progression and prognosis. Anticancer Res. 2010;30:4635–41.

    PubMed  Google Scholar 

  38. Woo DK, Kim HS, Lee HS, Kang YH, Yang HK, Kim WH. Altered expression and mutation of b-catenin gene in gastric carcinomas and cell lines. Int J Cancer. 2001;95:108–13.

    Article  PubMed  CAS  Google Scholar 

  39. Ramesh S, Nash J, McCulloch PG. Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer. Br J Cancer. 1999;81:1392–7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Gabbert HE, Mueller W, Schneiders A, Meier S, Moll R, Birchmeier W, et al. Prognostic value of E-cadherin expression in 413 gastric carcinomas. Int J Cancer. 1996;69:184–9.

    Article  PubMed  CAS  Google Scholar 

  41. Shun CT, Wu MS, Lin JT, Wang HP, Houng RL, Lee WJ, et al. An immunohistochemical study of E-cadherin expression with correlations to clinicopathological features in gastric cancer. Hepatogastroenterology. 1998;45:944–9.

    PubMed  CAS  Google Scholar 

  42. Chan AO, Lam SK, Chu KM, Lam CM, Kwok E, Leung SY, et al. Soluble E-cadherin is a valid prognostic marker in gastric carcinoma. Gut. 2001;48:808–11.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Fang DC, Luo YH, Yang SM, Li XA, Ling XL, Fang L. Mutation analysis of APC gene in gastric cancer with microsatellite instability. World J Gastroenterol. 2002;8:787–91.

    PubMed  CAS  Google Scholar 

  44. Samowitz WS, Slattery ML, Sweeney C, Herrick J, Wolff RK, Albertsen H. APC mutations and other genetic and epigenetic changes in colon cancer. Mol Cancer Res. 2007;5:165–70.

    Article  PubMed  CAS  Google Scholar 

  45. Arnold CN, Goel A, Niedzwiecki D, Dowell JM. APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q. Cancer Biol Therapy. 2004;3:960–4.

    Article  CAS  Google Scholar 

  46. Shin CM, Kim N, Jung Y, Park JH, Kang GH, Kim JS, et al. Role of Helicobacter pylori infection in aberrant DNA methylation along multistep gastric carcinogenesis. Cancer Sci. 2010;10:1337–46.

    Article  CAS  Google Scholar 

  47. Lee SH, Kang HJ, Shin DH, Cho DY, Song JM, Lee HC, et al. Expression of beta-catenin and its mechanism of delocalization in intestinal-type early gastric cancer based on mucin expression. Histol Histopathol. 2009;24:831–8.

    PubMed  CAS  Google Scholar 

  48. Hosoya K, Yamashita S, Ando T, Nakajima T, Itoh F, Ushijima T. Adenomatous polyposis coli 1A is likely to be methylated as a passenger in human gastric carcinogenesis. Cancer Lett. 2009;285(2):182–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Tunisian Ministry of Higher Education and Scientific Research. The authors would like to thank the technicians from the Department of Anatomo-pathology of CHU Habib Bourguiba for the technical assistance in IHC.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, 3038, Sfax, Tunisia

    Dorra Ben Ayed-Guerfali, Basma Hassairi, Ali Gargouri & Raja Mokdad-Gargouri

  2. Department of Anatomo-pathology, Habib Bourguiba Hospital, Sfax, Tunisia

    Abdelmajid Khabir & Tahia Sellami-Boudawara

Authors
  1. Dorra Ben Ayed-Guerfali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Basma Hassairi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdelmajid Khabir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tahia Sellami-Boudawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ali Gargouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Raja Mokdad-Gargouri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raja Mokdad-Gargouri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ayed-Guerfali, D.B., Hassairi, B., Khabir, A. et al. Expression of APC, β-catenin and E-cadherin in Tunisian patients with gastric adenocarcinoma: clinical significance. Tumor Biol. 35, 1775–1783 (2014). https://doi.org/10.1007/s13277-013-1236-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-1236-7

Keywords

Search

Navigation