Human Gene Set: MILICIC_FAMILIAL_ADENOMATOUS_POLYPOSIS_DN


Standard name MILICIC_FAMILIAL_ADENOMATOUS_POLYPOSIS_DN
Systematic name M6706
Brief description Top genes down-regulated in colon epithelium biopsies from FAP (familial adenomatous polyposis) patients with mutated APC [GeneID=324].
Full description or abstract P-cadherin is normally expressed in the basal layer of squamous epithelia and absent from the healthy intestine and colon. We have previously shown it to be expressed in all inflamed, hyperplastic, and dysplastic intestinal and colonic mucosa. This study aimed to better understand the mechanisms controlling the expression of P-cadherin and the biological effects of its ectopic presence in the intestine and colon. We investigated the CpG methylation status of the P-cadherin (CDH3) promoter and P-cadherin mRNA and protein expression in cases of familial and sporadic colorectal cancer (CRC). The CDH3 promoter was hypomethylated in colonic aberrant crypt foci, in CRC, and, occasionally, in the normal epithelium adjacent to cancer, demonstrating a potential field effect of cancerization. The hypomethylation was also associated with induction of P-cadherin expression in the neoplastic colon (P < 0.0001). We then created transgenic mice that overexpressed P-cadherin specifically in the intestinal and colonic epithelium under the liver fatty acid binding protein promoter. Forced ectopic expression of P-cadherin accompanied by indomethacin-induced inflammation resulted in a 3-fold higher crypt fission rate within the small and large intestines in the homozygous mice compared with the wild-type animals (P < 0.02). We conclude that epigenetic demethylation of the P-cadherin promoter in the human intestine permits its ectopic expression very early in the colorectal adenoma-carcinoma sequence and persists during invasive cancer. Induced P-cadherin expression, especially in mucosal damage, leads to an increased rate of crypt fission, a common feature of clonal expansion in gastrointestinal dysplasia.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 18829530   Authors: Milicic A,Harrison LA,Goodlad RA,Hardy RG,Nicholson AM,Presz M,Sieber O,Santander S,Pringle JH,Mandir N,East P,Obszynska J,Sanders S,Piazuelo E,Shaw J,Harrison R,Tomlinson IP,McDonald SA,Wright NA,Jankowski JA
Exact source Table 1: Log2 ratio < 0
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Source species Homo sapiens
Contributed by Jessica Robertson (MSigDB Team)
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identifier namespace		 HUMAN_GENE_SYMBOL
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Version history 3.0: First introduced

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