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

我们之前的研究表明，EGF以剂量依赖性的方式增强口腔鳞状细胞癌细胞系的随机运动性，并且暴露于EGF会增加相同细胞的尿激酶型纤溶酶原激活剂和基质金属蛋白酶-9的产生。这些结果强烈提示EGF可能促进人口腔鳞状细胞癌的侵袭和转移。在本项目中，为了揭示细胞运动的信号通路及其信号通路的抑制作用，我们从对EGF刺激最敏感的Ca9-22细胞系中建立了s-1克隆细胞，并建立了对EGF刺激最不敏感的i-1克隆细胞。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关系，随后通过erbB同型二聚体引起PLCr的激活和/或erbB3异源二聚体引起pi3激酶的激活，PKC被激活。此外，erbB同二聚体通过激活PLC激活nPKCd， erbB/erbB-3异二聚体通过激活PI3K激活aPKCe。这些结果表明，抑制aPKCe或nPKCd可减少人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益的模型。此外，aPKCe和nPKCd作为新靶点分子的候选分子被关闭。特别是这些分子比最近开发的分子靶向药物EGF受体、PI3K等具有更高的特异性。

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.