The participation of p53 independent pathway in the process of oral carcinogenesis

p53缺失小鼠（p53^<-/->）和野生型小鼠（WT）经致癌物处理后，对舌组织进行组织学检查。此外，我们还研究了细胞周期调节因子mrna和蛋白的表达变化以及Rb的磷酸化。我们还研究了ATM、p53和MDM2的表达与人口腔白斑上皮异常增生的关系。实验结果如下：1。在p53^<-/->和WT小鼠中，致癌物处理均引起上皮发育不良，如上皮增厚和基底细胞极性丧失，并且随着时间的推移，这些变化变得显性。在p53^<-/->小鼠中，致癌物处理后，WT小鼠p21 mRNA及其蛋白表达增加，而致癌物处理后，p53^<-/->小鼠p21表达未增加。2 .致癌物治疗1周后WT小鼠p53表达升高，治疗3周后p53表达降低。经致癌物处理的WT小鼠Rb蛋白发生磷酸化，但Rb蛋白的数量未发生变化。E2F的表达无明显变化。在口腔白斑中，p53的表达随着上皮发育不良的分级而增强，而在口腔癌中的表达减弱。ATM与上皮异常增生的相关性未见。MDM2在口腔白斑中的表达与上皮发育不良程度相关，且在口腔癌中的表达增强，提示p53依赖通路可能参与口腔癌的早期发生，而p53独立通路可能参与口腔癌的晚期发生。

p53 deficient mice (p53^<-/->) and wild type mice (WT) were treated with carcinogens, and their tongue tissues were examined histologically. Further, changes in the expression of mRNAs and protein of cell-cycle regulators and the phosphorylation of Rb were investigated. The correlation between the expression of ATM, p53 and MDM2 and epithelial dysplasia was also studied in human oral leukoplakia.The results obtained were as follows :1. Both in p53^<-/-> and WT mice, epithelial dysplasia such as thickening of the epithelial layer and loss of basal cell polarity were induced by the treatment of carcinogens and these changes become dominant with time.2. In WT mice, the expression of p21 mRNA and its protein was increased by the treatment of carcinogens, whereas the expression of p21 was not increased by the treatment of carcinogens in p53^<-/-> mice. The expression of p53 in WT mice was increased 1 week after the treatment of carcinogens, but its expression was decreased 3 weeks after the treatment.3. Phosphorylation of Rb protein was found in WT mice treated with carcinogens, though the amount of Rb protein was not changed. The expression of E2F was not also changed.4. In oral leukoplakia, the expression of p53 becomes strong with the grade of epithelial dysplasia, but its expression in oral cancer become weaker. The correlation between ATM and epithelial dysplasia was not seen. The expression of MDM2 in oral leukoplakia was correlated with the grade of epithelial dysplasia, and its expression become stronger in oral cancer..These results indicate that p53 dependent pathway may be concerned in the early stage of oral carcinogenesis and p53 independent pathway may participate in late stage of oral carcinogenesis.