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Mutant p53 in colon cancer
Mizuho Nakayama 1,2 and Masanobu Oshima 1,2,*
1 Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
2 WPI-Nano Life Science Institute, Kanazawa University, Kanazawa, 920-1192, Japan
*Correspondence to:Masanobu Oshima, E-mail: oshimam@staff.kanazawa-u.ac.jp
J Mol Cell Biol, Volume 11, Issue 4, April 2019, Pages 267-276  https://doi.org/10.1093/jmcb/mjy075
Keyword: colon cancer, missense-type mutant p53, gain-of-function, mouse model, NF-κB, multistep tumorigenesis, organoids

The accumulation of genetic alterations in driver genes is responsible for the development and malignant progression of colorectal cancer. Comprehensive genome analyses have revealed the driver genes, including APC, KRAS, TGFBR2, and TP53, whose mutations are frequently found in human colorectal cancers. Among them, the p53 mutation is found in ~60% of colorectal cancers, and a majority of mutations are missense-type at ‘hot spots’, suggesting an oncogenic role of mutant p53 by ‘gain-of-function’ mechanisms. Mouse model studies have shown that one of these missense-type mutations, p53 R270H (corresponding to human R273H), causes submucosal invasion of intestinal tumors, while the loss of wild-type p53 has a limited effect on the invasion process. Furthermore, the same mutant p53 promotes metastasis when combined with Kras activation and TGF-β suppression. Importantly, either missense-type p53 mutation or loss of wild-type p53 induces NF-κB activation by a variety of mechanisms, such as increasing promoter accessibility by chromatin remodeling, which may contribute to progression to epithelial–mesenchymal transition. These results indicate that missense-type p53 mutations together with loss of wild-type p53 accelerate the late stage of colorectal cancer progression through the activation of both oncogenic and inflammatory pathways. Accordingly, the suppression of the mutant p53 function via the inhibition of nuclear accumulation is expected to be an effective strategy against malignant progression of colorectal cancer.