Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer

MingZhou Guo, Michael House, Hiromu Suzuki, Ying Ye, Malcolm V. Brock, Fengmin Lu, Zhihua Liu, Anil K. Rustgi, James G. Herman

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

CDX2, a mammalian homologue of the homeobox gene 'caudal,' is expressed in gut epithelia and plays an important role in establishing the intestinal phenotype during development. Mice heterozygously disrupted for CDX2 develop disorganized polypoid hamartomas with glandular epithelium and stratified squamous metaplasia resembling foregut mucosa. Since no genetic disruptions of CDX2 have been reported to explain loss of gene function, we examined whether epigenetic mechanisms altered CDX2 expression. Eleven of 17 squamous esophageal cancer cell lines lacked expression of CDX2 that was restored following treatment with 5-aza-2′-deoxycytidine, while all colorectal cancer cell lines expressed CDX2. Loss of expression was associated with DNA methylation in the 5′ region of CDX2 determined by methylation specific PCR and bisulfite sequencing. Methylation of CDX2 was rare in primary colorectal (1 of 44 tumors, 2%) and esophageal adenocarcinoma neoplasms (2 of 43 tumors, 5%), but was common in esophageal squamous carcinoma (24 of 45 tumors, 49%). No CDX2 methylation was found in normal tissues. Using semi-quantitative RT-PCR, expression of CDX2 was found in low level in normal esophagus, at higher levels in primary adenocarcinoma of the esophagus, but not in primary squamous cancers of the esophagus. Restoration of CDX2 in silenced cell lines resulted in expression of the CDX2 target gene MUC2, a gene important in glandular differentiation. Our results suggest that the inactivation of CDX2 in esophageal cancer associated with DNA methylation may be an important determinant of the squamous or non-adenomatous phenotype.

Original languageEnglish (US)
Pages (from-to)1219-1226
Number of pages8
JournalInternational Journal of Cancer
Volume121
Issue number6
DOIs
StatePublished - Sep 15 2007
Externally publishedYes

Fingerprint

Esophageal Neoplasms
Epigenomics
Methylation
decitabine
DNA Methylation
Cell Line
Epithelium
Genes
Phenotype
Neoplasms
Polymerase Chain Reaction
Hamartoma
Homeobox Genes
Metaplasia
Esophagus
Squamous Cell Carcinoma
Colorectal Neoplasms
Mucous Membrane
Adenocarcinoma

Keywords

  • Cancer epigenetics
  • CDX2
  • Colon cancer
  • DNA methylation
  • Esophageal cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Guo, M., House, M., Suzuki, H., Ye, Y., Brock, M. V., Lu, F., ... Herman, J. G. (2007). Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer. International Journal of Cancer, 121(6), 1219-1226. https://doi.org/10.1002/ijc.22828

Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer. / Guo, MingZhou; House, Michael; Suzuki, Hiromu; Ye, Ying; Brock, Malcolm V.; Lu, Fengmin; Liu, Zhihua; Rustgi, Anil K.; Herman, James G.

In: International Journal of Cancer, Vol. 121, No. 6, 15.09.2007, p. 1219-1226.

Research output: Contribution to journalArticle

Guo, M, House, M, Suzuki, H, Ye, Y, Brock, MV, Lu, F, Liu, Z, Rustgi, AK & Herman, JG 2007, 'Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer', International Journal of Cancer, vol. 121, no. 6, pp. 1219-1226. https://doi.org/10.1002/ijc.22828
Guo, MingZhou ; House, Michael ; Suzuki, Hiromu ; Ye, Ying ; Brock, Malcolm V. ; Lu, Fengmin ; Liu, Zhihua ; Rustgi, Anil K. ; Herman, James G. / Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer. In: International Journal of Cancer. 2007 ; Vol. 121, No. 6. pp. 1219-1226.
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