Journal of Gastrointestinal Cancer

, Volume 47, Issue 1, pp 20–26 | Cite as

Downregulated Expression of E-cadherin and TP53 in Patients with Gastric Diseases: the Involvement of H. pylori Infection and Its Virulence Markers

  • Mariane Avante Ferraz
  • Luanna Munhoz Zabaglia
  • Weendelly Nayara Pereira
  • Wilson Aparecido Orcini
  • Roger Willian de Labio
  • Agostinho Caleman Neto
  • Fernanda Wisnieski
  • Danielle Queiroz Calcagno
  • Leonardo Caires Santos
  • Paulo Pimentel Assumpção
  • Rommel Rodriguez Burbano
  • Ricardo Artigiani
  • Marilia de Arruda Cardoso Smith
  • Spencer Luiz Marques Payão
  • Lucas T. RasmussenEmail author
Original Research



Gastritis caused by infection with Helicobacter pylori is characterized by chronic inflammation and damage in gastric tissue, which is a main risk factor for gastric cancer. Associated with H. pylori, the TP53 gene tumor suppressor and the cell adhesion glycoprotein epithelial cadherin develop a relevant role in the integrity and carcinogenesis of the epithelium. We aimed to detection of H. pylori and its main virulence markers and measured the messenger RNA (mRNA) expression levels of E-cadherin and TP53 genes.


The detection of H. pylori and its virulence markers, as well as the mRNA expression levels of E-cadherin and TP53 genes, were obtained for 161 samples of gastric biopsies including 37 with normal gastric tissue, 70 with gastritis, 24 from neoplastic tissue, and 27 from adjacent non-neoplastic by means of a quantitative real-time polymerase chain reaction.


The mRNA expression levels of E-cadherin and TP53 were found to be decreased in patients with gastritis, independently of H. pylori infection. In samples from gastric patients, the neoplastic tissue showed an accentuated decrease of expression; on the other hand, the expression of E-cadherin was normal in adjacent non-neoplastic.


No evidence was found of the involvement of the cagA and vacA genes in the decreased expression of E-cadherin and TP53. The process of carcinogenesis is complex, and the decrease of the E-cadherin gene expression and TP53 gene expression appears to contribute significantly.


E-cadherin Gastric cancer Gene expression Helicobacter pylori TP53 


Compliance with Ethical Standards

Conflict of Interests

The authors declare that there is no conflict of interests.

Funding Information

The authors would like to thank the São Paulo Research Foundation (FAPESP) for the funding of this research (grant numbers 20012/18333-3, 2013/21224-4, and 2013/21285-3).


  1. 1.
    Murakami M, Fukuzawa M, Yamamoto M, Hamaya K, Tamura Y, Sugiyama A, et al. Effects of Helicobacter pylori infection on gastric parietal cells and E-cadherin in Mongolian gerbils. J Pharmacol Sci. 2013;121(4):305–11.CrossRefPubMedGoogle Scholar
  2. 2.
    Schildberg CW, Abba M, Merkel S, Agaimy A, Dimmler A, Schlabrakowski A, et al. Gastric cancer patients less than 50 years of age exhibit significant downregulation of E-cadherin and CDX2 compared to older reference populations. Adv Med Sci. 2014;59(1):142–6. doi: 10.1016/j.advms.2014.03.002.CrossRefPubMedGoogle Scholar
  3. 3.
    Yang YL, Chen MW, Xian L. Prognostic and clinicopathological significance of downregulated e-cadherin expression in patients with Non-Small Cell Lung Cancer (NSCLC): a meta-analysis. PLoS One. 2014;9(6):e99763. doi: 10.1371/journal.pone.0099763.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta. 1994;1198(1):11–26.PubMedGoogle Scholar
  5. 5.
    Lazar D, Taban S, Sporea I, Dema A, Cornianu M, Lazar E, et al. The immunohistochemical expression of the p53-protein in gastric carcinomas. Correlation with clinicopathological factors and survival of patients. Romanian J Morphol Embryol Rev Roum Morphol Embryol. 2010;51(2):249–57.Google Scholar
  6. 6.
    Kim JH, Choi YJ, Lee SH, Shin HS, Lee IO, Kim YJ, et al. Effect of Helicobacter pylori infection on the sonic hedgehog signaling pathway in gastric cancer cells. Oncol Rep. 2010;23(6):1523–8.PubMedGoogle Scholar
  7. 7.
    Santos JC, Ladeira MS, Pedrazzoli Jr J, Ribeiro ML. Relationship of IL-1 and TNF-alpha polymorphisms with Helicobacter pylori in gastric diseases in a Brazilian population. Braz J Med Biol Res / Rev Bras Pesqui Med Biol / Soc Bras Biofisica. 2012;45(9):811–7.Google Scholar
  8. 8.
    Dong L, Zhu J, Wen X, Jiang T, Chen Y. Involvement of SET in the Wnt signaling pathway and the development of human colorectal cancer. Oncol Lett. 2014;7(4):1203–8. doi: 10.3892/ol.2014.1866.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Yu XW, Xu Q, Xu Y, Gong YH, Yuan Y. Expression of the E-cadherin/beta-catenin/tcf-4 pathway in gastric diseases with relation to Helicobacter pylori infection: clinical and pathological implications. Asian Pac J Cancer Prev : APJCP. 2014;15(1):215–20.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhu Y, Zhou X, Wu J, Su J, Zhang G. Risk factors and prevalence of helicobacter pylori infection in persistent high incidence area of gastric carcinoma in Yangzhong City. Gastroenterol Res Pract. 2014;2014:481365. doi: 10.1155/2014/481365.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52(24):6735–40.PubMedGoogle Scholar
  12. 12.
    Weydig C, Starzinski-Powitz A, Carra G, Lower J, Wessler S. CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res. 2007;313(16):3459–71. doi: 10.1016/j.yexcr.2007.07.015.CrossRefPubMedGoogle Scholar
  13. 13.
    Watanabe T, Asano N, Fichtner-Feigl S, Gorelick PL, Tsuji Y, Matsumoto Y, et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest. 2010;120(5):1645–62. doi: 10.1172/JCI39481.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Stolte M, Meining A. The updated Sydney system: classification and grading of gastritis as the basis of diagnosis and treatment. Can J Gastroenterol J Can Gastroenterol. 2001;15(9):591–8.Google Scholar
  15. 15.
    Scholte GH, van Doorn LJ, Quint WG, Lindeman J. Polymerase chain reaction for the detection of Helicobacter pylori in formaldehyde-sublimate fixed, paraffin-embedded gastric biopsies. Diagn Mol Pathol Amer J Sur Pathol B. 1997;6(4):238–43.CrossRefGoogle Scholar
  16. 16.
    Pereira WN, Ferraz MA, Zabaglia LM, de Labio RW, Orcini WO, Ximenez JPB, Neto AC, Payão SLM, Rasmussen L (2014) Association among H. pylori virulence markers dupA, cagA and vacA in Brazilian patients. J Venomous Anim Toxins Incl Trop Dis 20 (1):5Google Scholar
  17. 17.
    van Doorn LJ, Figueiredo C, Rossau R, Jannes G, van Asbroek M, Sousa JC, et al. Typing of Helicobacter pylori vacA gene and detection of cagA gene by PCR and reverse hybridization. J Clin Microbiol. 1998;36(5):1271–6.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Gomes LI, Rocha GA, Rocha AM, Soares TF, Oliveira CA, Bittencourt PF, et al. Lack of association between Helicobacter pylori infection with dupA-positive strains and gastroduodenal diseases in Brazilian patients. Int J Med Microbiol : IJMM. 2008;298(3–4):223–30. doi: 10.1016/j.ijmm.2007.05.006.CrossRefPubMedGoogle Scholar
  19. 19.
    Atherton JC, Peek Jr RM, Tham KT, Cover TL, Blaser MJ. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology. 1997;112(1):92–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Rasmussen LT, de Labio RW, Neto AC, Silva LC, Queiroz VF, Smith MAC, et al. Detection of Helicobacter pylori in gastric biopsies, saliva and dental plaques of dyspeptic patients from Marília, São Paulo, Brazil: presence of vacA and cagA genes. J Venomous Anim Toxins Incl Trop Dis. 2012;18(2):7. doi: 10.1590/S1678-91992012000200008.Google Scholar
  21. 21.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. doi: 10.1006/meth.2001.1262.CrossRefPubMedGoogle Scholar
  22. 22.
    Hoy B, Lower M, Weydig C, Carra G, Tegtmeyer N, Geppert T, et al. Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep. 2010;11(10):798–804. doi: 10.1038/embor.2010.114.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Wroblewski LE, Shen L, Ogden S, Romero-Gallo J, Lapierre LA, Israel DA, et al. Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology. 2009;136(1):236–46. doi: 10.1053/j.gastro.2008.10.011.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene. 2007;26(32):4617–26. doi: 10.1038/sj.onc.1210251.CrossRefPubMedGoogle Scholar
  25. 25.
    Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest. 2004;113(3):321–33. doi: 10.1172/JCI20925.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Peek Jr RM, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol. 2006;208(2):233–48. doi: 10.1002/path.1868.CrossRefPubMedGoogle Scholar
  27. 27.
    Li T, Chen J, Liu QL, Huo ZH, Wang ZW. Meta-analysis: E-cadherin immunoexpression as a potential prognosis biomarker related to gastric cancer metastasis in Asian patients. Eur Rev Med Pharmacol Sci. 2014;18(18):2693–703.PubMedGoogle Scholar
  28. 28.
    Liu Y, Chen XG, Liang CZ. Expressions of E-cadherin and N-cadherin in prostate cancer and their implications. Zhonghua Nan Ke Xue Natl J Androl. 2014;20(9):781–6.Google Scholar
  29. 29.
    Mehendiratta M, Solomon MC, Boaz K, Guddattu V, Mohindra A. Clinico-pathological correlation of E-cadherin expression at the invasive tumor front of Indian oral squamous cell carcinomas: an immunohistochemical study. J Oral Maxillofac Pathol : JOMFP. 2014;18(2):217–22. doi: 10.4103/0973-029X.140753.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Lim SO, Gu JM, Kim MS, Kim HS, Park YN, Park CK, et al. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology. 2008;135(6):2128–40. doi: 10.1053/j.gastro.2008.07.027. 2140 e2121-2128.CrossRefPubMedGoogle Scholar
  31. 31.
    Wu X, Zhuang YX, Hong CQ, Chen JY, You YJ, Zhang F, et al. Clinical importance and therapeutic implication of E-cadherin gene methylation in human ovarian cancer. Med Oncol. 2014;31(8):100. doi: 10.1007/s12032-014-0100-y.CrossRefPubMedGoogle Scholar
  32. 32.
    Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, et al. ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A. 2005;102(26):9182–7. doi: 10.1073/pnas.0500918102.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Mayerle J, Schnekenburger J, Kruger B, Kellermann J, Ruthenburger M, Weiss FU, et al. Extracellular cleavage of E-cadherin by leukocyte elastase during acute experimental pancreatitis in rats. Gastroenterology. 2005;129(4):1251–67. doi: 10.1053/j.gastro.2005.08.002.CrossRefPubMedGoogle Scholar
  34. 34.
    Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J, et al. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol. 2002;4(3):222–31. doi: 10.1038/ncb758.CrossRefPubMedGoogle Scholar
  35. 35.
    Wei J, Noto JM, Zaika E, Romero-Gallo J, Piazuelo MB, Schneider B, et al. Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut. 2014. doi: 10.1136/gutjnl-2014-307295.Google Scholar
  36. 36.
    Karim S, Ali A. Correlation of p53 over-expression and alteration in p53 gene detected by polymerase chain reaction-single strand conformation polymorphism in adenocarcinoma of gastric cancer patients from India. World J Gastroenterol : WJG. 2009;15(11):1381–7.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Ierardi E, Di Leo A, Barone M, Marangi S, Burattini O, Panarese A, et al. Tumor necrosis factor alpha and apoptosis in Helicobacter pylori related progressive gastric damage: a possible mechanism of immune system involvement in epithelial turnover regulation. Immunopharmacol Immunotoxicol. 2003;25(2):203–11.CrossRefPubMedGoogle Scholar
  38. 38.
    Kulak K, Bobinski M, Polak G, Jedrych BJ, Kotarski J, Bednarek W. Expression of caspase 9 and p53 in uterine leiomyosarcomas. Ginekol Pol. 2014;85(8):600–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Mariane Avante Ferraz
    • 1
  • Luanna Munhoz Zabaglia
    • 1
  • Weendelly Nayara Pereira
    • 1
  • Wilson Aparecido Orcini
    • 1
  • Roger Willian de Labio
    • 2
  • Agostinho Caleman Neto
    • 2
  • Fernanda Wisnieski
    • 3
  • Danielle Queiroz Calcagno
    • 3
  • Leonardo Caires Santos
    • 3
  • Paulo Pimentel Assumpção
    • 4
  • Rommel Rodriguez Burbano
    • 5
  • Ricardo Artigiani
    • 6
  • Marilia de Arruda Cardoso Smith
    • 3
  • Spencer Luiz Marques Payão
    • 1
  • Lucas T. Rasmussen
    • 1
    Email author
  1. 1.Pró-Reitoria de Pesquisa e Pós-GraduaçãoUniversidade do Sagrado CoraçãoBauruBrazil
  2. 2.Departamento de Genética e Biologia Molecular, HemocentroFaculdade de Medicina de MaríliaMaríliaBrazil
  3. 3.Disciplina de Genética, Departamento de Morfologia e GenéticaUniversidade Federal de São PauloSão PauloBrazil
  4. 4.Núcleo de Pesquisa em Oncologia, Hospital João de Barros BarretoUniversidade Federal do ParáBelémBrazil
  5. 5.Laboratório de Citogenética Humana, Instituto de Ciências BiológicasUniversidade Federal do ParáBelémBrazil
  6. 6.Departamento de PatologiaUniversidade Federal de São PauloSão PauloBrazil

Personalised recommendations