Document Type : Original Research
Authors
1 Histopathology Department, Pathology Lab, Rizgary Teaching Hospital, Erbil, Iraq
2 Department of Basic Sciences/Pathology, College of Medicine, Hawler Medical University, Erbil, Iraq
Abstract
Background & Objective: Gastric cancer (GC) persists to be a major health issue globally, and the need to investigate new molecular markers for improving the survival of patients continues. CDX2 is a homeobox caudal protein family member encoded by the CDX2 gene and is probably playing a role in intestinal epithelial differentiation and proliferation. This study aimed to assess the expression of this protein in gastric cancer cells in addition to its correlation with multiple clinicopathological parameters.
Methods: This observational retrospective study was carried out on 80 gastric cancer cases in Erbil, Iraq. CDX2 protein immunoexpression in tumor cells, as well as its correlation with several clinicopathological criteria, were investigated.
Results: CDX2 was detected in 38.75% of GC patients. We found a significant correlation between CDX2 expression and the age of patients (P=0.02). Even though the protein was more expressed in tumors with negative lymphovascular invasion and intestinal GC, there was no significant correlation between the expression of this protein and invasion. In addition, CDX2 expression was not significantly correlated with patient gender, tumor grade, nodal status, and tumor stage.
Conclusion: CDX2 expression was observed to be downregulated in younger patients. It could be due to the higher frequency of diffuse GC, in which CDX2 is expressed less than the intestinal type, in younger individuals.
Highlights
- A significant correlation was detected between the age of patientsand CDX2 expression in tumor cells.
- A non-significant negative relationship although not statistically significant, was noted between lymphovascular invasion and CDX2 expression.
- CDX2 expression was detected more in the intestinal-type gastric carcinomas.
- We observed no significant correlation between CDX2 expression and the gender of patients.
Keywords
Main Subjects
- Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. [DOI:10.3322/caac.21492] [PMID]
- Khoshnaw N, Mohammed HA, Abdullah DA. Patterns of Cancer in Kurdistan - Results of Eight Years Cancer Registration in Sulaymaniyah Province-Kurdistan-Iraq. Asian Pac J Cancer Prev. 2015;16(18):8525-31. [DOI:10.7314/APJCP.2015.16.18.8525] [PMID]
- 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] [PMID]
- Correa P, Piazuelo MB. The gastric precancerous cascade. J Dig Dis. 2012;13(1):2-9. [DOI:10.1111/j.1751-2980.2011.00550.x] [PMID] [PMCID]
- Lauren P. The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification. Acta Pathol Microbiol Scand. 1965;64:31-49. [DOI:10.1111/apm.1965.64.1.31] [PMID]
- Bai ZG, Ye YJ, Shen DH, Lu YY, Zhang ZT, Wang S. PTEN expression and suppression of proliferation are associated with Cdx2 overexpression in gastric cancer cells. Int J Oncol. 2013;42(5):1682-91. [DOI:10.3892/ijo.2013.1875] [PMID]
- Sakaguchi T, Gu X, Golden HM, Suh E, Rhoads DB, Reinecker HC. Cloning of the human claudin-2 5'-flanking region revealed a TATA-less promoter with conserved binding sites in mouse and human for caudal-related homeodomain proteins and hepatocyte nuclear factor-1alpha. J Biol Chem. 2002;277(24):21361-70. [DOI:10.1074/jbc.M110261200] [PMID]
- Hinoi T, Lucas PC, Kuick R, Hanash S, Cho KR, Fearon ER. CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology. 2002;123(5):1565-77. [DOI:10.1053/gast.2002.36598] [PMID]
- Funakoshi S, Ezaki T, Kong J, Guo RJ, Lynch JP. Repression of the desmocollin 2 gene expression in human colon cancer cells is relieved by the homeodomain transcription factors Cdx1 and Cdx2. Mol Cancer Res. 2008;6(9):1478-90. [DOI:10.1158/1541-7786.MCR-07-2161] [PMID]
- Drummond F, Putt W, Fox M, Edwards YH. Cloning and chromosome assignment of the human CDX2 gene. Ann Hum Genet. 1997;61(Pt 5):393-400. [DOI:10.1017/S0003480097006465] [PMID]
- Qin R, Wang NN, Chu J, Wang X. Expression and significance of homeodomain protein Cdx2 in gastric carcinoma and precancerous lesions. World J Gastroenterol. 2012;18(25):3296-302.
- Slik K, Turkki R, Carpen O, Kurki S, Korkeila E, Sundstrom J, et al. CDX2 Loss With Microsatellite Stable Phenotype Predicts Poor Clinical Outcome in Stage II Colorectal Carcinoma. Am J Surg Pathol. 2019;43(11):1473-82. [DOI:10.1097/PAS.0000000000001356] [PMID]
- Yan LH, Wei WY, Xie YB, Xiao Q. New insights into the functions and localization of the homeotic gene CDX2 in gastric cancer. World J Gastroenterol. 2014;20(14):3960-6. [DOI:10.3748/wjg.v20.i14.3960] [PMID] [PMCID]
- Saberi S, Esmaeili M, Tashakoripour M, Hosseini ME, Baharvand H, Mohammadi M. 2021.
- Barros R, Pereira B, Duluc I, Azevedo M, Mendes N, Camilo V, et al. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines. J Pathol. 2008;215(4):411-20. [DOI:10.1002/path.2369] [PMID]
- Bleuming SA, Kodach LL, Garcia Leon MJ, Richel DJ, Peppelenbosch MP, Reitsma PH, et al. Altered bone morphogenetic protein signalling in the Helicobacter pylori-infected stomach. J Pathol. 2006;209(2):190-7. [DOI:10.1002/path.1976] [PMID]
- Yuan T, Ni Z, Han C, Min Y, Sun N, Liu C, et al. SOX2 interferes with the function of CDX2 in bile acid-induced gastric intestinal metaplasia. Cancer Cell Int. 2019;19:24. [DOI:10.1186/s12935-019-0739-8] [PMID] [PMCID]
- Liu Q, Teh M, Ito K, Shah N, Ito Y, Yeoh KG. CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer. Mod Pathol. 2007;20(12):1286-97. [DOI:10.1038/modpathol.3800968] [PMID]
- Kwon OK, Kim SW, Chae HD, Ryu SW, Chung HY, Kim SW, et al. Validation of the 7th AJCC/UICC staging system for gastric cancer and a proposal for a new TNM system based on a prognostic score: a retrospective multicenter study. Ann Surg Treat Res. 2016;91(6):295-302. [DOI:10.4174/astr.2016.91.6.295] [PMID] [PMCID]
- Park DY, Srivastava A, Kim GH, Mino-Kenudson M, Deshpande V, Zukerberg LR, et al. CDX2 expression in the intestinal-type gastric epithelial neoplasia: frequency and significance. Mod Pathol. 2010;23(1):54-61. [DOI:10.1038/modpathol.2009.135] [PMID]
- Saito M, Okayama H, Saito K, Ando J, Kumamoto K, Nakamura I, et al. CDX2 is involved in microRNA-associated inflammatory carcinogenesis in gastric cancer. Oncol Lett. 2017;14(5):6184-90. [DOI:10.3892/ol.2017.6956] [PMID] [PMCID]
- Zhang X, Tsukamoto T, Mizoshita T, Ban H, Suzuki H, Toyoda T, et al. Expression of osteopontin and CDX2: indications of phenotypes and prognosis in advanced gastric cancer. Oncol Rep. 2009;21(3):609-13. [DOI:10.3892/or_00000263]
- Takami H, Sentani K, Matsuda M, Oue N, Sakamoto N, Yasui W. Cytokeratin expression profiling in gastric carcinoma: clinicopathologic significance and comparison with tumor-associated molecules. Pathobiology. 2012;79(3):154-61. [DOI:10.1159/000335694] [PMID]
- Ha Kim G, Am Song G, Youn Park D, Han Lee S, Hyun Lee D, Oh Kim T, et al. CDX2 expression is increased in gastric cancers with less invasiveness and intestinal mucin phenotype. Scand J Gastroenterol. 2006;41(8):880-6. [DOI:10.1080/00365520500497140] [PMID]
- Okayama H, Kumamoto K, Saitou K, Hayase S, Kofunato Y, Sato Y, et al. CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer. Oncol Rep. 2009;22(4):745-55. [DOI:10.3892/or_00000496] [PMID]
- Halder A, Kundu M, Das RN, Chatterjee U, Datta C, Choudhuri MK, et al. CDX2 Expression in Gastric Carcinoma: A Clinicopathological Study. Indian J Med Paediatr Oncol. 2021;39(01):52-7. [DOI:10.4103/ijmpo.ijmpo_49_17]
- Song X, Chen HX, Wang XY, Deng XY, Xi YX, He Q, et al. H. pylori-encoded CagA disrupts tight junctions and induces invasiveness of AGS gastric carcinoma cells via Cdx2-dependent targeting of Claudin-2. Cell Immunol. 2013;286(1-2):22-30. [DOI:10.1016/j.cellimm.2013.10.008] [PMID]
- Zhang Y, Wang H, Bi C, Xiao Y, Liu Z. Expression of CDX2 in gastric cardia adenocarcinoma and its correlation with H. pylori and cell proliferation. Oncotarget. 2016;7(34): 54973-82. [DOI:10.18632/oncotarget.10362] [PMID] [PMCID]
- Hryniuk A, Grainger S, Savory JG, Lohnes D. Cdx1 and Cdx2 function as tumor suppressors. J Biol Chem. 2014;289(48):33343-54. [PMID] [PMCID] [DOI:10.1074/jbc.M114.583823]
- Camilo V, Barros R, Celestino R, Castro P, Vieira J, Teixeira MR, et al. Immunohistochemical molecular phenotypes of gastric cancer based on SOX2 and CDX2 predict patient outcome. BMC Cancer. 2014;14:753. [DOI:10.1186/1471-2407-14-753] [PMID] [PMCID]
- Wang Y, Jiang R, Wang Q, Li Y, Sun Z, Zhao H. Silencing LINC01021 inhibits gastric cancer through upregulation of KISS1 expression by blocking CDK2-dependent phosphorylation of CDX2. Mol Ther Nucleic Acids. 2021;24:832-44. [DOI:10.1016/j.omtn.2021.01.025] [PMID] [PMCID]
- Dizeyi T, Al-Rawi R, Ismael A. Immunohistochemical expression of CDX2 gene in colorectal carcinoma. Zanco J Med Sci. 2019;23 (1):106-12. [DOI:10.15218/zjms.2019.014]
- Chai D, Du H, Li K, Zhang X, Li X, Zhao X, et al. CDX2 and Reg IV expression and correlation in gastric cancer. BMC Gastroenterol. 2021;21 (1):92. [DOI:10.1186/s12876-021-01678-9] [PMID] [PMCID]
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