Cyclin D1 Overexpression Increases Susceptibility to 4-Nitroquinoline-1-Oxide-Induced Dysplasia and Neoplasia in Murine Squamous Oral Epithelium
Cyclin D1 Overexpression Increases Susceptibility to 4-Nitroquinoline-1-Oxide-Induced Dysplasia and Neoplasia in Murine Squamous Oral Epithelium
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DOI：
10.1002/mc.20531
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发表时间：
2009-09-01
影响因子：
4.6
通讯作者：
Mallya, Sanjay M.
中科院分区：
文献类型：
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作者：
Wilkey, Jonathan F.;Buchberger, Glenn;Mallya, Sanjay M.
细胞周期蛋白D1癌基因在口腔鳞状细胞癌中经常被扩增/过表达。以舌头、食道和前胃的复层鳞状上皮为靶点的细胞周期蛋白D1过表达的小鼠在这些部位形成上皮异型增生的表型。在这项研究中，我们使用4-硝基喹啉-1-氧化物(4NQO)，一种已被证实的强效口腔致癌物，研究了细胞周期蛋白D1过表达对小鼠致癌易感性的影响。高表达细胞周期蛋白D1的小鼠和非转基因小鼠被给予4NQO(饮用水中百万分之20或50)8wk，并监测另外16wk。舌头的组织病理学分析显示，与非转基因对照组和未经处理的对照组相比，过表达细胞周期蛋白D1的小鼠的异型增生严重程度明显更高。此外，只有细胞周期蛋白D1过表达的小鼠出现了口部食道上皮的肿瘤性病变。对异常增生性和肿瘤性病变的检查显示异常增殖。我们的研究结果表明，细胞周期蛋白D1的过度表达增加了致癌物诱导的口腔肿瘤发生的易感性。这些结果强调了细胞周期蛋白D1在口腔肿瘤发生发展过程中的重要性。此外，他们强调了这种转基因模型在研究口腔癌前病变和癌症发病机制方面的价值，并将其建立为测试上消化道癌症化学预防候选药物的模型系统。(C)2009年Wiley-Liss，Inc.
The cyclin D1 oncogene is frequently amplified/overexpressed in oral squamous cell carcinomas. Mice with overexpression of cyclin D1 targeted to the stratified squamous epithelia of the tongue, esophagus, and forestomach develop a phenotype of epithelial dysplasia at these sites. in this study, we examined the effect of cyclin D1 overexpression on susceptibility of mice to carcinogen-induced tumorigenesis, using 4-nitroquinoline-1-oxide (4NQO), an established potent oral carcinogen in mice. Cyclin D1 overexpressing mice and nontransgenic littermates were administered 4NQO (20 or 50 parts per million (ppm) in the drinking water) for 8 wk and monitored for an additional 16 wk. Histopathological analyses of the tongue revealed significantly higher severity of dysplasia in the cyclin D1 overexpression mice, compared with nontransgenic controls and with untreated controls. Moreover, only the cyclin D1 overexpression mice developed neoplastic lesions in the oro-esophageal epithelia. Examination of the dysplastic and neoplastic lesions revealed abnormal proliferation. Our findings suggest that cyclin D1 overexpression enhances susceptibility to carcinogen-induced oral tumorigenesis. These results underscore the importance of cyclin D1 in the process of oral neoplastic development. Further, they emphasize the value of this transgenic model to study the pathogenesis of oral precancer and cancer and establish it as a model system to test candidate agents for chemoprevention of upper aero-digestive cancer. (C) 2009 Wiley-Liss, Inc.