The effects of CDK inhibitors and PI3 kinase related kinase on the carcinogenesis from precancerous lesions

我们研究了MDM2和PI3蛋白在口腔白斑、口腔癌和正常口腔黏膜上皮中的表达。结果表明：1.MDM2在口腔白斑中的表达与上皮异型增生程度有关，而在口腔癌中的表达弱于伴有重度异型增生的口腔白斑。CDK抑制因子p21在伴有中、重度异型增生的口腔白斑中均有表达。但在正常上皮和癌组织中未见表达。PI3激酶相关蛋白(ATM、ATR、DNA-PK)表达于整个上皮细胞的胞浆中。4NQO给药10d后，从小鼠舌或腭部获取口腔角质形成细胞，用RT-PCR方法检测CDK抑制物基因表达。结果表明，野生型小鼠角质形成细胞中可诱导出p21和p27mRNAs，而p53基因敲除小鼠的角质形成细胞中不能诱导它们的表达。用4NQO诱导野生鼠角质形成细胞中细胞周期蛋白D、CDK4和p16mRNAs的表达，结果表明，致癌刺激不仅能诱导细胞增殖因子Cyclin和CDK，而且还能诱导抑制细胞增殖的CDK抑制基因。

We investigated the expression of MDM2 and PI3 kinase related kinase proteins in cases with oral leukoplakia and oral cancer, and normal epithelium. Further, changes in the gene expression of INK4 and p21 families was examined in oral keratinocytes of p53 knockout and wild mice.The results obtained were as follows :1. The expression of MDM2 in oral leukoplakia was correlated with the grade of epithelial dysplasia, whereas that in oral cancer was weaker than that in oral leukoplakia with severe dysplasia. The expression of p21, a CDK inhibitor, was found in oral leukoplakias with moderate and severe epithelial dysplasia. However, it was not observed in normal epithelia and cancer tissues.2. PI3 kinase related kinases (ATM, ATR, DNA-PK) were expressed in the cytoplasm of whole epithelial cells.3. At 10 days after 4NQO administration, oral keratinocytes were obtained from mouse tongue or palate and the gene expression of CDK inhibitors was analyzed by RT-PCR method. The results revealed that p21 and p27 mRNAs were induced in keratinocytes of wild mice, but that they were not induced in those of p53 knockout mice.4. Cyclin D, CDK4 and p16 mRNAs were induced by 4NQO treatment in keratinocytes of wild mice.These results indicate that stimulation for carcinogenesis not only induces cell proliferating factors such as Cyclin and CDK, but also induces the CDK inhibitor genes which suppress cell proliferation.