Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice.
Targeted expression of ornithine decarboxylase antizyme prevents upper aerodigestive tract carcinogenesis in p53-deficient mice.
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DOI：
10.1093/carcin/bgs377
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发表时间：
2013-03
期刊：
影响因子：
4.7
通讯作者：
D. Feith;A. Pegg;L. Fong
中科院分区：
文献类型：
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作者：
D. Feith;A. Pegg;L. Fong
口腔和食管的上呼吸消化道（UADT）癌症是一个重大的全球健康负担，迫切需要开发相关的动物模型，以确定化学预防和治疗策略，以打击这些疾病。抗酶（AZ）是细胞多胺水平的多功能负调节剂，在这里，我们评估角蛋白5（K5）-AZ转基因小鼠对肿瘤模型的易感性，该模型将联合收割机化学致癌作用与已知影响人类对UADT癌症易感性并促进小鼠UADT致癌作用的饮食和遗传风险因素相结合。首先，将p53（+/-）和K5-AZ/p53（+/-）（AZ/p53（+/-））小鼠置于锌缺乏（ZD）或锌充足（ZS）饮食中并长期暴露于4-硝基喹啉1-氧化物。与p53（+/-）相比，ZD和ZS AZ/p53（+/-）小鼠的舌肿瘤发生率、多样性和大小均显著降低。AZ表达还降低了原位癌或浸润性癌的进展，并降低了鳞状细胞癌生物标志物K14、环氧合酶-2和金属硫蛋白的表达。接下来，将AZ表达p53（+/-）和p53缺失小鼠置于ZD饮食中并用单剂量的N-亚硝基甲基苄胺处理。无论p53的状态，前胃（FST）肿瘤的发病率，多样性和大小大大减少AZ表达，这也与FST上皮厚度的显着减少沿着减少增殖标记K6和增加分化标记兜甲蛋白。这些研究证明了靶向AZ表达在两种不同和独特的小鼠模型中的强大肿瘤抑制作用，并验证了多胺代谢途径作为UADT癌症化学预防的靶点。
Upper aerodigestive tract (UADT) cancers of the oral cavity and esophagus are a significant global health burden, and there is an urgent need to develop relevant animal models to identify chemopreventive and therapeutic strategies to combat these diseases. Antizyme (AZ) is a multifunctional negative regulator of cellular polyamine levels, and here, we evaluate the susceptibility of keratin 5 (K5)-AZ transgenic mice to tumor models that combine chemical carcinogenesis with dietary and genetic risk factors known to influence human susceptibility to UADT cancer and promote UADT carcinogenesis in mice. First, p53(+/-) and K5-AZ/p53(+/-) (AZ/p53(+/-)) mice were placed on a zinc-deficient (ZD) or zinc-sufficient (ZS) diet and chronically exposed to 4-nitroquinoline 1-oxide. Tongue tumor incidence, multiplicity and size were substantially reduced in both ZD and ZS AZ/p53(+/-) mice compared with p53(+/-). AZ expression also reduced progression to carcinoma in situ or invasive carcinoma and decreased expression of the squamous cell carcinoma biomarkers K14, cyclooxygenase-2 and metallothionein. Next, AZ-expressing p53(+/-) and p53 null mice were placed on the ZD diet and treated with a single dose of N-nitrosomethylbenzylamine. Regardless of p53 status, forestomach (FST) tumor incidence, multiplicity and size were greatly reduced with AZ expression, which was also associated with a significant decrease in FST epithelial thickness along with reduced proliferation marker K6 and increased differentiation marker loricrin. These studies demonstrate the powerful tumor suppressive effects of targeted AZ expression in two distinct and unique mouse models and validate the polyamine metabolic pathway as a target for chemoprevention of UADT cancers.