GST-p and p53 in 4NQO-induced tongue carcinomas of two strains of rats

采用4-硝基喹啉1-氧化物（4NQO）处理大鼠两株[Dark-Agouti （DA）和Wistar/Furth （WF）大鼠]，研究了p53蛋白在大鼠舌癌发生过程中的免疫组化表达。设计了动物实验，以两种不同的方式观察两种菌株之间的致癌性差异，即4NQO治疗持续到死亡状态或使用确定的治疗计划。尽管免疫组化结果显示，在DA大鼠和WF大鼠建立的SCCs中p53蛋白的阳性比例相似，但在发育不良的舌上皮中，通常随机分布的p53阳性细胞簇在DA大鼠中的数量多于WF大鼠。DA大鼠的p53反应性比WF早，实验后期DA大鼠的p53阳性簇数明显增加，而WF大鼠的p53阳性簇数似乎没有变化。7只DA大鼠和2只WF大鼠舌组织DNA样本（13.4%）显示p53基因阳性突变。在所有9只大鼠中，外显子5（密码子174处TGC _3 TAC转位）发生了非常常见的基因突变。综上所述，64.3%舌部p53蛋白免疫组化阳性的大鼠出现了一些p53基因突变。其余35.7%（5只DA大鼠）在舌黏膜中有p53蛋白阳性簇，然而，它们没有显示任何可检测到的p53基因突变。因此，目前的结果可能表明，尽管p53基因突变缺失，p53蛋白异常在大鼠舌癌发生的早期阶段发挥了一些重要作用。这些结果也提示，DA大鼠和WF大鼠对4NQO的p53反应可能存在品系差异，这些差异可能导致致癌性的差异。

Immunohistochemical expression of p53 protein during rat lingual carcinogenesis was studied using two strains of rats [Dark-Agouti (DA) and Wistar/Furth (WF) rats] treated with 4-nitroquinoline 1-oxide (4NQO). Animal experiments were designed to look into differences in carcinogenesity between the two strains in two different fashions, i.e. 4NQO treatment being lasted until the moribund state or using a defined treatment schedule. Although the immunohistochemical results showed that the positive ratio of p53 protein in the established SCCs was similar between DA and WF rats, the clusters of p53 positive cells, usually situated in radom groups in the dysplastic lingual epithelium, were greater in numbers in DA rats than in WF.Reactivity of p53 in DA rats was detected earlier than that in WF, and marked increase of p53 positive clusters in DA rats was noted at the later stages of the experiment, whereas in WF rats the number of p53 positive clusters seemed to be unchanged. It was also demonstrated that DNA samples of the tongue tissues of 7 DA and 2 WF rats (13.4%) showed positive mutations in p53 gene. A very common gene mutation was observed in exon 5 (TGC _3 TAC transitions at codon 174) in all 9 rats. In summary, 64.3 % of the rats with immunohistochemically positive p53 protein in the tongue exhibited some p53 gene mutations. The remaining 35.7 % (5 DA rats) had p53 protein positive clusters in their lingual mucosae, however, they did not show any detectable p53 gene mutations. Thus, the present results may suggest p53 protein abnormalities play some important roles at the earlier stages of rat lingual carcinogenesis inspite of the absence of p53 gene mutations. These results also suggest that there may be strain differences in the p53 response to 4NQO between DA and WF rats, and these differences may contribute to the contrasting carcinogenesity.