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Ectopic Expression of P-Cadherin Correlates with Promoter Hypomethylation Early in Colorectal Carcinogenesis and Enhanced Intestinal Crypt Fission In vivo

¹ Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom; ² Digestive Diseases Centre and ³ Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, University of Leicester, Leicester, United Kingdom; ⁴ Histopathology Unit, ⁵ Molecular and Population Genetics, and ⁶ Bioinformatics and Biostatistics, Cancer Research UK, London Research Institute, London, United Kingdom; ⁷ Department of Surgery, Royal Infirmary, University of Edinburgh, Edinburgh, United Kingdom; and ⁸ Instituto Aragones de Ciencias de la Salud, CIBERehd, Zaragoza, Spain

Requests for reprints: Janusz Jankowski, Digestive Diseases Center, 4th floor Windsor Building, Leicester Royal Infirmary, Leicester, LE1 5WW, England, United Kingdom. Phone: 44-116-2047850; Fax: 44-1865-616022; E-mail: janusz.jankowski{at}uhl-tr.nhs.uk.

Key Words: colorectal cancer • P-cadherin • stem cells • hypomethylation • crypt bifurcation

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. [Cancer Res 2008;68(19):7760–8]

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