p53 Haploinsufficiency Profoundly Accelerates the Onset of Tongue Tumors in Mice Lacking the Xeroderma Pigmentosum Group A Gene

Ide, Fumio; Kitada, Munenori; Sakashita, Hideaki; Kusama, Kaoru; Tanaka, Kiyoji; Ishikawa, Takatoshi

doi:10.1016/s0002-9440(10)63531-6

Cited by 29 publications

(15 citation statements)

References 32 publications

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“…In a model of mice lacking the xeroderma pigmentosum group A gene (XPA Ϫ/Ϫ mice) and highly predisposed to tongue tumors when exposed to 4-nitroquinoline 1-oxide (4NQO), the p53 haploinsufficiency (TP53Ϫ/ϩ) and complete inactivation (TP53Ϫ/Ϫ) did not increase the incidence of cancer but accelerated dramatically tumor development. 23 In patients with Lynch syndrome, the Proline 72 variant of TP53 accelerates the age at colorectal cancer onset. 14,24 Pro/Pro genotype has also been associated with an earlier age at onset in pharynx, 25 larynx, 25,26 and oral cancer, 25 and in pulmonary cancer in African Americans 27 and Japanese patients.…”

Section: Resultsmentioning

confidence: 99%

TP53 codon 72 polymorphism is associated with age at onset of glioblastoma

Ducray¹,

Idbaïh²,

Marie³

et al. 2009

Neurology

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Section: Resultsmentioning

confidence: 99%

TP53 codon 72 polymorphism is associated with age at onset of glioblastoma

Ducray¹,

Idbaïh²,

Marie³

et al. 2009

Neurology

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“…In addition, Rowley et al (27) and Qin et al (28) reported that the p53 gene is an early target for mutation in oral tumor development, with mutations being detected in 40% to 50% of premalignant lesions and SCCs. More recently, Ide et al (29) found that p53 haploinsufficiency profoundly accelerates the onset of tongue tumors in mice lacking the xeroderma pigmentosum group A gene. All together, these results suggest that p53 plays a major and early role in head and neck tumor development.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Wang

Yao

et al. 2006

Molecular Cancer Research

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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.

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“…Several lines of evidence indicate that the histological and molecular changes induced by 4-NQO are similar to those found in human OPLs and OSCCs (22–25). The oral carcinogenesis process can be further accelerated by using mice with increased susceptibility to carcinogens, such as mice deficient for the tumor suppressor gene Trp53 (p53) (26, 27). Indeed, heterozygous p53 knockout mice (p53 +/− ) have been extensively used in chemoprevention studies for several carcinogen-induced malignancies (28).…”

Section: Introductionmentioning

confidence: 99%

PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions

Wang

Xie

Wang

et al. 2017

Cancer Prevention Research

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Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPLs). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-Nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti-PD-1 treatment significantly reduced the number of oral lesions that developed in these mice, and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8+ and CD4+ T cells and the accumulation of CTLA-4+ T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of interferon-γ, STAT1 activation and the production of the T cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T cell activation mediates the immunopreventive effects of anti-PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti-PD-1.

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p53 Haploinsufficiency Profoundly Accelerates the Onset of Tongue Tumors in Mice Lacking the Xeroderma Pigmentosum Group A Gene

Cited by 29 publications

References 32 publications

TP53 codon 72 polymorphism is associated with age at onset of glioblastoma

TP53 codon 72 polymorphism is associated with age at onset of glioblastoma

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

PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions

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