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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
29
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pubmed:dateCreated |
2006-7-6
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pubmed:abstractText |
Colorectal cancer is a major cause of cancer death worldwide. A number of key oncogenes and tumor suppressor genes have been proposed to drive progression from healthy colonic epithelia to malignant tumors, including members of the Wnt/beta-catenin pathway. Recently, CpG island promoter hypermethylation was shown to cause inactivation of two extracellular Wnt inhibitors in colon cancer: secreted frizzled-related proteins (sFRPs) and Wnt inhibitory factor-1 (WIF-1). Here, we show for the first time that another extracellular Wnt inhibitor, the DICKKOPF-1 (DKK-1) gene, is transcriptionally silenced by CpG island promoter hypermethylation in colon cancer cell lines (n=9), whereas treatment with the DNA-demethylating agent 5-aza-2-deoxycytidine restored DKK-1 expression. Restoration of DKK-1 function in non-expressing cells bearing a truncated APC (Adenomatous Polyposis Coli) gene had no effect on beta-catenin/T-cell factor-dependent transcription, but induced tumor suppressor-like features such as reduced colony formation density and tumor growth inhibition in nude mice. These results suggest additional functions for DKK-1 other than inhibiting canonical Wnt signaling. In primary colorectal tumors, DKK-1 was found hypermethylated in 17% (nine of 54) of cases. Furthermore, while for both SFRP-1 and WIF-1 methylation-associated silencing occurred across the whole spectrum of colorectal tumorigenesis, DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (Duke's C and D tumors).
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Adenomatous Polyposis Coli Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Antimetabolites, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/Azacitidine,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DKK1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Intercellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/WIF1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Wnt Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/decitabine
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0950-9232
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
6
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pubmed:volume |
25
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4116-21
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:16491118-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:16491118-Adenomatous Polyposis Coli Protein,
pubmed-meshheading:16491118-Animals,
pubmed-meshheading:16491118-Antimetabolites, Antineoplastic,
pubmed-meshheading:16491118-Azacitidine,
pubmed-meshheading:16491118-Carrier Proteins,
pubmed-meshheading:16491118-Cell Transformation, Neoplastic,
pubmed-meshheading:16491118-Colon,
pubmed-meshheading:16491118-Colorectal Neoplasms,
pubmed-meshheading:16491118-CpG Islands,
pubmed-meshheading:16491118-DNA Methylation,
pubmed-meshheading:16491118-Epigenesis, Genetic,
pubmed-meshheading:16491118-Epithelium,
pubmed-meshheading:16491118-Genes, Tumor Suppressor,
pubmed-meshheading:16491118-Humans,
pubmed-meshheading:16491118-Intercellular Signaling Peptides and Proteins,
pubmed-meshheading:16491118-Mice,
pubmed-meshheading:16491118-Mice, Nude,
pubmed-meshheading:16491118-Neoplasm Transplantation,
pubmed-meshheading:16491118-Promoter Regions, Genetic,
pubmed-meshheading:16491118-Repressor Proteins,
pubmed-meshheading:16491118-Signal Transduction,
pubmed-meshheading:16491118-Transplantation, Heterologous,
pubmed-meshheading:16491118-Wnt Proteins
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pubmed:year |
2006
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pubmed:articleTitle |
Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer.
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pubmed:affiliation |
Instituto de Investigaciones Biomédicas Alberto Sols and Departamento de Bioquímica, Facultad de Medicina, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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