Zhang Zhongqiu, Wang Yian, Yao Ruisheng, Li Jie, Lubet Ronald A, You Ming
Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Mol Cancer Res. 2006 Jun;4(6):401-10. 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.
在本研究中，我们使用携带显性负性p53突变（p53(Val135/WT)）的小鼠进行了生物测定，以评估种系p53突变是否使小鼠易患口腔鳞状细胞癌（SCC）。用4-硝基喹啉-1-氧化物处理小鼠口腔后，p53(Val135/WT)小鼠口腔、食管和前胃/胃的肿瘤发生率分别为66%、91%和20%。相比之下，野生型同窝小鼠（p53(WT/WT)）口腔、食管和前胃/胃的肿瘤发生率分别仅为25%、58%和4%。致癌物处理后，p53(Val135/WT)小鼠和p53(WT/WT)小鼠之间最显著的差异是，p53(Val135/WT)小鼠的SCC患病率更高，发展更快。为了确定肿瘤发生过程中涉及这些差异的精确基因或途径，我们检测了4-硝基喹啉-1-氧化物处理的p53(Val135/WT)和p53(WT/WT)小鼠正常舌组织以及舌SCC的基因表达谱。微阵列和GenMAPP分析显示，显性负性p53（(135)Valp53）影响SCC发生过程中的几个细胞过程。受影响的过程包括凋亡和细胞周期停滞途径，这些途径在肿瘤和正常上皮中均受到调节。这些结果表明，p53依赖的凋亡减少和细胞增殖增加可能导致p53(Val135/WT)小鼠口腔和胃食管恶性肿瘤的发生率增加，以及肿瘤生长和进展更快。
