Immunohistochemical expression of CDX2 gene in colorectal carcinoma
Keywords:Colorectal cancer, CDX2 expression, Immunohistochemistry
Background and objective: Colorectal cancer is a multi-factorial disease process, with etiology encompassing genetic factors, environmental exposures, and inflammatory conditions of the digestive tract. This study aimed to investigate the immunohistochemical expression of CDX2 as well as clinical and histopathological parameters of patients with colorectal cancer in Erbil, Kurdistan.
Methods: A retrospective study including about 100 colorectal cancer cases in Erbil city, Kurdistan was conducted from January 2015 to January 2017. Tumor type, site, size, histological grade, lymph node status, and pathological stage with CDX2 expression were investigated.
Results: CDX2 was expressed in 86 out of 100 (86%) patients. It was more expressed (focal or diffuse staining) in nonmucinous carcinoma more than signet ring and mucinous carcinoma. Loss of CDX2 expression in colorectal cancer is associated with a high tumor grade and stage. Significant associations between CDX2 expression with both tumor type and tumor grade were observed. Although CDX2 expression was found to be reduced in proximal location (right colon) and higher stage, however, no significant associations between CDX2 expressions in colorectal cancer were detected with tumor site, nodal status, and tumor stage.
Conclusion: Reduced and loss CDX2 expression in colorectal cancer associated with high tumor grades as well as with the mucinous and signet ring cell carcinomas may reflect aggressive tumor behavior probably because of the CDX2 tumor-inhibitory properties. However, the full extent of CDX2’s antitumor effects has yet to be elucidated.
Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin 2017; 67(3):177–93.
Othman RT, Abdulljabar R, Saeed A, Kittani SS, Sulaiman HM, Mohammed SA, et al. Cancer incidence rates in the Kurdistan region/Iraq from 2007-2009. Asian Pac J Cancer Prev 2011; 12(5):12614.
Boyle P, Leon ME. Epidemiology of colorectal cancer. Br Med Bull 2002; 64:1–25.
Jenkins D, Balsitis M, Gallivan S, Dixon MF, Gilmour HM, Shepherd NA, et al. Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. The British Society of Gastroenterology Initiative. J Clin Pathol 1997; 50(2):93–105.
Barbacid M. ras genes. Annu Rev Biochem 1987; 56:779–827.
Trinh KY, Jin T, Drucker DJ. Identification of domains mediating transcriptional activation and cytoplasmic export in the caudal homeobox protein Cdx-3. J Biol Chem 1999; 274(9):6011–9.
Silberg DG, Swain GP, Suh ER, Traber PG. Cdx1 and cdx2 expression during intestinal development. Gastroenterology 2000; 119(4):961–71.
Suh E, Traber PG. An intestine-specific homeobox gene regulates proliferation and differentiation. Mol Cell Biol 1996; 16(2):619–25.
Boyd M, Hansen M, Jensen TG, Perearnau A, Olsen AK, Bram LL, et al. Genome-wide analysis of CDX2 binding in intestinal epithelial cells (Caco-2). J Biol Chem 2010; 285(33):25115–25.
Freund JN, Domon-Dell C, Kedinger M, Duluc I. The Cdx-1 and Cdx-2 homeobox genes in the intestine. Biochem Cell Biol 1998; 76(6):957–69.
Guo RJ, Suh ER, Lynch JP. The role of Cdx proteins in intestinal development and cancer. Cancer Biol Ther 2004; 3(7):593–601.
Aoki K, Tamai Y, Horiike S, Oshima M, Taketo MM. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice. Nat Genet 2003; 35(4):323–30.
Bonhomme C, Duluc I, Martin E, Chawengsaksophak K, Chenard MP, Kedinger M, et al. The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development. Gut 2003; 52(10):1465–71.
Vang R, Gown AM, Wu LS, Barry TS, Wheeler DT, Yemelyanova A, et al. Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7. Mod Pathol 2006; 19(11):1421–8.
Bayrak R, Haltas H, Yenidunya S. The value of CDX2 and cytokeratins 7 and 20 expression in differentiating colorectal adenocarcinomas from extraintestinal gastrointestinal adenocarcinomas: cytokeratin 7-/20+ phenotype is more specific than CDX2 antibody. Diagn Pathol 2012; 7:9.
Kaimaktchiev V, Terracciano L, Tornillo L, Spichtin H, Stoios D, Bundi M, et al. The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas. Mod Pathol 2004; 17(11):1392–9.
Bakaris S, Cetinkaya A, Ezberci F, Ekerbicer H. Expression of homeodomain protein CDX2 in colorectal adenoma and adenocarcinoma. Histol Histopathol 2008; 23(9):1043–7.
Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol 2001; 159(6):2239–48.
Baba Y, Nosho K, Shima K, Freed E, Irahara N, Philips J, et al. Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer. Clin Cancer Res 2009; 15(14):4665–73.
Choi BJ, Kim CJ, Cho YG, Song JH, Kim SY, Nam SW, et al. Altered expression of CDX2 in colorectal cancers. APMIS 2006; 114(1):50–4.
Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, et al. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. N Engl J Med 2016; 374(3):211–22.
Bae JM, Lee TH, Cho NY, Kim TY, Kang GH. Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients. World J Gastroenterol 2015; 21(5):1457–67.
Olsen J, Espersen ML, Jess P, Kirkeby LT, Troelsen JT. The clinical perspectives of CDX2 expression in colorectal cancer: a qualitative systematic review. Surg Oncol 2014; 23(3):167–76.
De Lott LB, Morrison C, Suster S, Cohn DE, Frankel WL. CDX2 is a useful marker of intestinal-type differentiation: a tissue microarray-based study of 629 tumors from various sites. Arch Pathol Lab Med 2005; 129(9):1100–5.
Dawson H, Koelzer VH, Lukesch AC, Mallaev M, Inderbitzin D, Lugli A, et al. Loss of Cdx2 Expression in Primary Tumors and Lymph Node Metastases is Specific for Mismatch Repair-Deficiency in Colorectal Cancer. Front Oncol 2013; 3:265.
Gross I, Duluc I, Benameur T, Calon A, Martin E, Brabletz T, et al. The intestine-specific homeobox gene Cdx2 decreases mobility and antagonizes dissemination of colon cancer cells. Oncogene 2008; 27(1):107–15.
Mizoshita T, Inada K, Tsukamoto T, Kodera Y, Yamamura Y, Hirai T, et al. Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa--with special emphasis on participation in intestinal metaplasia of the human stomach. Gastric Cancer 2001; 4(4):185–91.
Bai YQ, Miyake S, Iwai T, Yuasa Y. CDX2, a homeobox transcription factor, upregulates transcription of the p21/WAF1/CIP1 gene. Oncogene 2003; 22(39):7942–9.
Suh E, Chen L, Taylor J, Traber PG. A homeodomain protein related to caudal regulates intestine-specific gene transcription. Mol Cell Biol 1994; 14(11):7340–51.
Witek ME, Nielson K, Walters R, Hyslop T, Palazzo J, Schulz S, et al. The putative tumor suppressor CDX2 is overexpressed by human colorectal adenocarcinomas. Clin Cancer Res 2005; 11:8549–56.
Almeida R, Silva E, Santos-Silva F, Silberg DG, Wang J, De Bolos C, et al. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol 2003; 199(1):36–40.
Winn B, Tavares R, Fanion J, Noble L, Gao J, Sabo E, et al. Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation. Hum Pathol 2009; 40:398–404.
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