BASIC RESEARCH OF ORAL CANCER THERAPY TARGETING TO THE EGF RECEPTOR AND ITS SIGNAL TRANSDUCTIONAL MOLECULES.

我们以前的研究表明，EGF以剂量依赖的方式增强口腔鳞癌细胞系的随机运动能力，并且EGF使同一细胞产生的尿激酶型纤溶酶原激活物和基质金属蛋白酶-9增加。这些结果强烈提示EGF可能促进口腔鳞癌的侵袭和转移。本课题从对表皮生长因子刺激最敏感的细胞株S-1克隆细胞和对表皮生长因子最不敏感的克隆细胞I-1克隆细胞中，建立了与细胞运动有关的信号通路和抑制信号通路的信号通路。使用S-1克隆细胞进行了进一步的研究。当EGF与EGF受体结合时，首先发生酪氨酸磷酸化，然后通过激活由erbB同源二聚体产生的PLCR和/或由erbB3异源二聚体产生的PI3-激酶来激活PKC。此外，erb B同源二聚体通过激活PLC来激活nPKCd，erb B/erbB-3异源二聚体通过激活PI3K来激活aPKCe。这些结果表明，抑制aPKCe或nPKCd可以减少口腔癌细胞的侵袭和转移，为分子靶向药物的研究提供了有用的模型。此外，aPKCe和nPKCd作为新的靶向分子的良好候选者被封闭。特别是，这些分子比新近开发的分子靶向药物EGF受体、PI3K等更具特异性。

Our previous studies revealed that EGF enhanced the random motility of oral squamous cell carcinoma cell lines in a dose-dependent fashion and exposure to EGF let to an increased production of urokinase type plasminogen activator and matrix metalloproteniase-9 by the same cells. These results strongly suggest the EGF may promote the invasion and metastasis of human oral squamous cell carcinomas. In this project, to reveal the signal pathway concerning the cell motility and inhibiting effects of signal pathway, we established s-1 clone cells from Ca9-22 cell line, which was most sensitive clone against the EGF stimulation and also we established i-1 clone cells, which was most insensitive clone. Further studies were done using s-1 clone cells. When EGF bind to the EGF receptor, tyrosine phosphorelation is firstly occurred and subsequently PKC is activated through the activation of PLCr arising from erbB homodimer and/or activation of PI3-kinase arising from erbB3 heterodimer. Furthermore, erbB homodimer activates the nPKCd through the activation of PLC and also erbB/erbB-3 heterodimer activates aPKCe through the activation of PI3K. These results suggest that inhibition of aPKCe or nPKCd can reduce the invasion and metastasis of human oral cancer cells and that the useful model in the investigations of molecular target medicines is possibly established. Furthermore, as an auspicious candidate of new target molecules, aPKCe and nPKCd were closed up. Especially, these molecles were more specific than EGF receptor, PI3K, and so on, which recently developed molecular target medicines.