Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium.
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 beta-catenin (exon 3), K-ras (codons 12/13) and p53 (exons 5-8) by sequencing and for cellular localization of beta-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). beta-Catenin mutations were present in 75% of lesions of p53+/+ mice and absent in lesions from p53-/- mice (P = 0.055). Nuclear expression of beta-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 beta-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.
Chang
Wen-Chi L
WC
Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. wen-chi.chang@fccc.edu
Coudry
Renata A
RA
Clapper
Margie L
ML
Zhang
Xiaoyan
X
Williams
Kara-Lynn
KL
Spittle
Cynthia S
CS
Li
Tianyu
T
Cooper
Harry S
HS
D000818:Animals; D003092:Colitis / Q000150:complications*; D015179:Colorectal Neoplasms / Q000150:complications*; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011123:Polyploidy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D016264:Dextran Sulfate