Expression of APC, β-catenin and E-cadherin in Tunisian patients with gastric adenocarcinoma: clinical significance
- 368 Downloads
- 6 Citations
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.
Keywords
Wnt signalling pathway APC β-Catenin E-cadherin Gastric cancerNotes
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
References
- 1.Parkin D, Bray F, Ferlay J, Pisani P. Global cancer statistics. CA Cancer J Clin. 2002;55:74–108.CrossRefGoogle Scholar
- 2.Jang BG, Kim WH. Molecular pathology of gastric carcinoma. Pathobiology. 2011;78:302–10.PubMedCrossRefGoogle Scholar
- 3.Gumbiner BM. Signal transduction by b-catenin. Curr Opin Cell Biol. 1995;7:634–40.PubMedCrossRefGoogle Scholar
- 4.Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 2004;303:1483–7.PubMedCentralPubMedCrossRefGoogle Scholar
- 5.Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–51.PubMedGoogle Scholar
- 6.Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387–98.PubMedCrossRefGoogle Scholar
- 7.Jamora C, Fuchs E. Intercellular adhesion, signalling and the cytoskeleton. Nat Cell Biol. 2002;4:101–8.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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).Google Scholar
- 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.CrossRefGoogle 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.PubMedCrossRefGoogle Scholar
- 18.Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol. 1998;153:333–9.PubMedCentralPubMedCrossRefGoogle Scholar
- 19.Gumbiner BM. Regulation of cadherin adhesive activity. J Cell Biol. 2000;148:399–404.PubMedCentralPubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCentralPubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCentralPubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCentralPubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCentralPubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCentralPubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle Scholar