J Korean Med Sci.  2011 May;26(5):647-653. 10.3346/jkms.2011.26.5.647.

CDX1 and CDX2 Expression in Intestinal Metaplasia, Dysplasia and Gastric Cancer

• Kang JM
• Lee BH
• Kim N
• Lee HS
• Lee HE
• Park JH
• Kim JS
• Jung HC
• Song IS

• KMID: 1777864
• DOI: http://doi.org/10.3346/jkms.2011.26.5.647

Abstract

Intestinal metaplasia (IM) has been regarded as a premalignant condition. However, the pathogenesis of IM is not fully understood. The aim of this study was to evaluate the role of CDX1 and CDX2 in the formation of IM and the progression to dysplasia and gastric cancer (GC). A total of 270 subjects included 90 with GC, dysplasia and age- and sex-matched controls. Real-time PCR (RT-PCR) was performed with body specimens for CDX1 and CDX2. The expression of CDX2 was significantly higher in H. pylori positive group than H. pylori negative group (P = 0.045). CDX1 and CDX2 expression increased proportional to the IM grade of the body (P < 0.001). CDX2 expression was significantly higher in incomplete type of IM than in complete type (P = 0.045). The expression of CDX1 in dysplasia group was significantly higher than in the control group (P = 0.001); in addition, CDX1 and CDX2 in cancer group was significantly higher than control group (P < 0.001, and P < 0.001, respectively). Aberrant expression of CDX1 and CDX2 correlated with H. pylori infection and grade of IM in the body. Furthermore, the results suggest that CDX1 and CDX2 play a role in the progression to GC and dysplasia.

Keyword

CDX1; CDX2; Intestinal Metaplasia; Stomach Neoplasms; Dysplasia

MeSH Terms

Aged
Female
Helicobacter Infections/complications/microbiology
Helicobacter pylori/isolation & purification
Homeodomain Proteins/*genetics/metabolism
Humans
Intestinal Diseases/*genetics/microbiology/pathology
Male
Metaplasia/pathology
Middle Aged
Polymerase Chain Reaction
Precancerous Conditions/metabolism/pathology
Stomach Neoplasms/etiology/*genetics/microbiology

Figure

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  Fig. 1 Correlation between CDX1 and CDX2 expression and grade of intestinal metaplasia. CDX1 in the antrum (A) and body (B), CDX2 in the antrum (C) and body (D). r, correlation coefficient.

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  Fig. 2 The comparison of the CDX1 and CDX2 expression according to disease group. The relative mRNA expression of the CDX1 (A) and CDX2 (B) of dysplasia and gastric cancer groups with the control group. Data are presented as means ± standard error.

Reference

1. Correa P. A human model of gastric carcinogenesis. Cancer Res. 1988. 48:3554–3560.

2. Filipe MI, Potet F, Bogomoletz WV, Dawson PA, Fabiani B, Chauveinc P, Fenzy A, Gazzard B, Goldfain D, Zeegen R. Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancer. Preliminary data from a prospective study from three centres. Gut. 1985. 26:1319–1326.

3. El-Zimaity HM, Ota H, Graham DY, Akamatsu T, Katsuyama T. Patterns of gastric atrophy in intestinal type gastric carcinoma. Cancer. 2002. 94:1428–1436.

4. Iida F, Kusama J. Gastric carcinoma and intestinal metaplasia. Significance of types of intestinal metaplasia upon development of gastric carcinoma. Cancer. 1982. 50:2854–2858.

5. Silberg DG, Swain GP, Suh ER, Traber PG. Cdx1 and cdx2 expression during intestinal development. Gastroenterology. 2000. 119:961–971.

6. Suh E, Chen L, Taylor J, Traber PG. A homeodomain protein related to caudal regulates intestine-specific gene transcription. Mol Cell Biol. 1994. 14:7340–7351.

7. Almeida R, Silva E, Santos-Silva F, Silberg DG, Wang J, De Bolós C, David L. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol. 2003. 199:36–40.

8. Silberg DG, Sullivan J, Kang E, Swain GP, Moffett J, Sund NJ, Sackett SD, Kaestner KH. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology. 2002. 122:689–696.

9. Silberg DG, Furth EE, Taylor JK, Schuck T, Chiou T, Traber PG. CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium. Gastroenterology. 1997. 113:478–486.

10. Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K, Sugano K. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia. J Gastroenterol. 2002. 37:94–100.

11. Seno H, Oshima M, Taniguchi MA, Usami K, Ishikawa TO, Chiba T, Taketo MM. CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer: prognostic implications. Int J Oncol. 2002. 21:769–774.

12. Kim MJ. The usefulness of CDX-2 for differentiating primary and metastatic ovarian carcinoma: an immunohistochemical study using a tissue microarray. J Korean Med Sci. 2005. 20:643–648.

13. Kim HS, Lee JS, Freund JN, Min KW, Kim W, Juhng SW, Park CS. CDX-2 homeobox gene expression in human gastric carcinoma and precursor lesions. J Gastroenterol Hepatol. 2006. 21:438–442.

14. Bai YQ, Yamamoto H, Akiyama Y, Tanaka H, Takizawa T, Koike M, Kenji Yagi O, Saitoh K, Takeshita K, Iwai T, Yuasa Y. Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach. Cancer Lett. 2002. 176:47–55.

15. Shiotani A, Haruma K, Uedo N, Iishi H, Ishihara R, Tatsuta M, Kumamoto M, Nakae Y, Ishiguro S, Graham DY. Histological risk markers for non-cardia early gastric cancer. Pattern of mucin expression and gastric cancer. Virchows Arch. 2006. 449:652–659.

16. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992. 52:6735–6740.

17. 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. 20:1286–1297.

18. Satoh K, Mutoh H, Eda A, Yanaka I, Osawa H, Honda S, Kawata H, Kihira K, Sugano K. Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori. Helicobacter. 2002. 7:192–198.

19. Mizoshita T, Inada K, Tsukamoto T, Kodera Y, Yamamura Y, Hirai T, Kato T, Joh T, Itoh M, Tatematsu M. 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. 4:185–191.

20. Mutoh H, Sakurai S, Satoh K, Osawa H, Hakamata Y, Takeuchi T, Sugano K. Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice. Gut. 2004. 53:1416–1423.

21. Shiotani A, Iishi H, Uedo N, Ishihara R, Ishiguro S, Tatsuta M, Nakae Y, Kumamoto M, Hinoi T, Merchant JL. Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression. Aliment Pharmacol Ther. 2006. 24:Suppl 4. 71–80.

22. Kim GH, Song GA, Park DY, Lee SH, Lee DH, Kim TO, Jo HJ, Heo J, Kang DH, Cho M. CDX2 expression is increased in gastric cancers with less invasiveness and intestinal mucin phenotype. Scand J Gastroenterol. 2006. 41:880–886.

23. Mizoshita T, Tsukamoto T, Nakanishi H, Inada K, Ogasawara N, Joh T, Itoh M, Yamamura Y, Tatematsu M. Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol. 2003. 129:727–734.

24. Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H, Tomiyama T, Sato Y, Yamamoto H, Isoda N, Yoshida T, Ido K, Sugano K. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 2004. 64:7740–7747.

25. Bonhomme C, Duluc I, Martin E, Chawengsaksophak K, Chenard MP, Kedinger M, Beck F, Freund JN, Domon-Dell C. The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development. Gut. 2003. 52:1465–1471.

26. Witek ME, Nielsen K, Walters R, Hyslop T, Palazzo J, Schulz S, Waldman SA. The putative tumor suppressor Cdx2 is overexpressed by human colorectal adenocarcinomas. Clin Cancer Res. 2005. 11:8549–8556.

27. Rugge M, Ingravallo G, Farinati F, Russo VM, Zaninotto G, Alvisi V. Re: CDX2 homeotic gene expression in gastric noninvasive neoplasia. Am J Surg Pathol. 2004. 28:834–835.

28. Barros R, Marcos N, Reis CA, De Luca A, David L, Almeida R. CDX2 expression is induced by Helicobacter pylori in AGS cells. Scand J Gastroenterol. 2009. 44:124–125.

29. Vauhkonen M, Vauhkonen H, Sipponen P. Helicobacter pylori infection induces a reversible expression of the CDX2 transcription factor protein in human gastric epithelium. Scand J Gastroenterol. 2008. 43:915–921.

30. Shiotani A, Uedo N, Iishi H, Tatsuta M, Ishiguro S, Nakae Y, Kamada T, Haruma K, Merchant JL. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. Int J Cancer. 2007. 121:1182–1189.