Carcinogenesis Advance Access published online on June 8, 2007
Carcinogenesis, doi:10.1093/carcin/bgm134
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Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium
1 Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA 19111
2 Division of Medical Science, Fox Chase Cancer Center, Philadelphia, PA 19111
* To whom requests for reprints should be addressed: Wen-Chi L. Chang, Ph.D., Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, Phone: 215-728-5368, FAX: 215-214-1622, E-mail: 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 3 or 4 cycles of dextran sulfate sodium 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, while 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 dextran sulfate sodium model.
Received January 24, 2007; revised May 11, 2007; accepted May 29, 2007.
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