Loss of CDX1 expression in colorectal carcinoma: Promoter methylation, mutation, and loss of heterozygosity analyses of 37 cell lines
- 2 January 2004
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 101 (2) , 574-579
- https://doi.org/10.1073/pnas.0307190101
Abstract
Expression of the homeobox protein CDX1 is lost or reduced in a significant proportion of colorectal carcinomas (CRCs) but the underlying mechanism for this is unclear. We have demonstrated absence of CDX1 mRNA expression in 7 of 37 CRC cell lines and shown that all 7 cell lines have a methylated CDX1 promoter. Twenty-five cell lines showed both CDX1 mRNA expression and an unmethylated CDX1 promoter. The five remaining cell lines had a partially methylated CDX1 promoter and all expressed CDX1 mRNA; when treated with the demethylating agent, 5-aza-2'-deoxycytidine, these five cell lines all showed increased CDX1 expression. No mutations were found in the promoter and coding regions of CDX1. One polymorphism was demonstrated in each of the promoter, 5' UTR, and coding region of exon 1 of CDX1, but there were no associations between CDX1 mRNA expression and different polymorphic genotypes. Similarly, there was no association between CDX1 mRNA expression and loss of heterozygosity at the CDX1 locus. In conclusion, absence or reduction of CDX1 expression in CRC seems to be primarily regulated by promoter methylation and is probably selected for because of its impact on the differentiation of colonocytes.Keywords
This publication has 13 references indexed in Scilit:
- DNA Methylation Down-regulates CDX1 Gene Expression in Colorectal Cancer Cell LinesJournal of Biological Chemistry, 2002
- Gene silencing in mammalian cells and the spread of DNA methylationOncogene, 2002
- Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model systemGut, 2002
- Methylation and colorectal cancerThe Journal of Pathology, 2001
- Correlations of partial and extensive methylation at the p14ARF locus with reduced mRNA expression in colorectal cancer cell lines and clinicopathological features in primary tumorsCarcinogenesis: Integrative Cancer Research, 2000
- Deregulated Expression of Homeobox-Containing Genes, HOXB6, B8, C8, C9, and Cdx-1, in Human Colon Cancer Cell LinesBiochemical and Biophysical Research Communications, 2000
- DNA Methylation Is the Primary Silencing Mechanism for a Set of Germ Line- and Tumor-Specific Genes with a CpG-Rich PromoterMolecular and Cellular Biology, 1999
- TheCdx-1andCdx-2homeobox genes in the intestineBiochemistry and Cell Biology, 1998
- CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epitheliumGastroenterology, 1997
- A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands.Proceedings of the National Academy of Sciences, 1992