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Carcinogenesis Advance Access originally published online on June 8, 2007
Carcinogenesis 2007 28(11):2375-2381; doi:10.1093/carcin/bgm134
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium

Wen-Chi L. Chang*, Renata A. Coudry, Margie L. Clapper, Xiaoyan Zhang, Kara-Lynn Williams, Cynthia S. Spittle, Tianyu Li and Harry S. Cooper1

Division of Population Science
1 Division of Medical Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

* To whom correspondence should be addressed. Tel: +1 215 728 5368; Fax: +1 215 214 1622; Email: wen-chi.chang{at}fccc.edu

Loss of p53 function is an early event in colitis-associated neoplasia in humans. We assessed the role of p53 in a mouse model of colitis-associated neoplasia. Colitis was induced in p53–/–, p53+/– and p53+/+ mice using three or four cycles of dextran sulfate sodium (DSS) followed by 120 days of water. Mice were examined for incidence, multiplicity and types of neoplastic lesions. Lesions were examined for mutations in ß-catenin (exon 3), K-ras (codons 12/13) and p53 (exons 5–8) by sequencing and for cellular localization of ß-catenin by immunohistochemistry. The incidence of neoplastic lesions was 57, 20 and 20% in p53–/–, p53+/– and p53+/+ mice, respectively (P = 0.013). p53–/– mice had a greater number of total lesions (P < 0.0001), cancers (P = 0.001) and dysplasias (P = 0.009) per mouse than either p53+/– or p53+/+ mice. Flat lesions were associated with the p53–/– genotype, whereas polypoid lesions were associated with the p53+/– and p53+/+ genotypes (P < 0.0001). ß-Catenin mutations were present in 75% of lesions of p53+/+ mice and absent in lesions from p53–/– mice (P = 0.055). Nuclear expression of ß-catenin was seen only in polypoid lesions (91%). No K-ras or p53 mutations were detected. These data indicate that loss of p53 enhances the induction of colitis-associated neoplasia, particularly flat lesions, and dysregulation of ß-catenin signaling plays an important role in the formation of polypoid lesions in this mouse model. As observed in humans, p53 plays a protective role in colitis-associated neoplasia in the DSS model.

Abbreviations: CRC, colorectal cancer; DSS, dextran sulfate sodium; PCR, polymerase chain reaction; UC, ulcerative colitis; PGE2, prostaglandin E2

Received January 24, 2007; revised May 11, 2007; accepted May 29, 2007.


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