p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer

• Published in: Molecular cancer research Vol. 4; no. 6; pp. 401 - 410
• Main Authors: Zhang, Zhongqiu, Wang, Yian, Yao, Ruisheng, Li, Jie, Lubet, Ronald A, You, Ming
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-06-2006
• Subjects: 4-Nitroquinoline-1-oxide; Animals; Apoptosis; cancer; carcinogen; Carcinogens; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - genetics; Cell Cycle; Disease Models, Animal; Genes, p53; Genetic Predisposition to Disease; Germ-Line Mutation; head and neck; Mice; Mice, Transgenic; mouse; Mouth Neoplasms - chemically induced; Mouth Neoplasms - etiology; Mouth Neoplasms - genetics; Mutation, Missense; Oligonucleotide Array Sequence Analysis; oral; Tongue Neoplasms - genetics
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-06-0028

In this study, we did a bioassay employing mice with a dominant-negative p53 mutation (p53 Val135/WT ) to assess whether a germ-line p53 mutation predisposed mice toward the development of squamous cell carcinomas (SCC) in
the oral cavity. Treatment of the mouse oral cavity with 4-nitroquinoline-1-oxide produced a 66%, 91%, and 20% tumor incidence
in the oral cavity, esophagus, and forestomach/stomach, respectively, in p53 Val135/WT mice. In contrast, only a 25%, 58%, and 4% tumor incidence was observed in oral cavity, esophagus, and forestomach/stomach,
respectively, in wild-type littermates (p53 WT/WT ). The most striking difference between p53 Val135/WT and p53 WT/WT mice following the carcinogen treatment was the higher prevalence and more rapid development of SSC in p53 Val135/WT mice than in wild-type mice. To identify the precise genes or pathways involved in these differences during tumor development,
we examined gene expression profiles of 4-nitroquinoline-1-oxide-treated normal tongues as well as tongue SCC in p53 Val135/WT and p53 WT/WT mice. Microarray and GenMAPP analysis revealed that dominant-negative p53 ( 135 Valp53) affects several cellular processes involved in SCC development. Affected processes included apoptosis and cell cycle
arrest pathways, which were modulated in both tumor and normal epithelium. These results showed that reduction of p53-dependent
apoptosis and increases in cell proliferation might contribute to the observed increase in oral cavity and gastroesophageal
malignancies in p53 Val135/WT mice as well as to the more rapid growth and progression of tumors. (Mol Cancer Res 2006;4(6):401–10)