ANALYSIS OF THE SIGNAL TRANSDUCTION OF CELL MOTILITY INDUCED BY EGF STIMULATION IN HUMAN ORAL CANCER CELLS

为了明确表皮生长因子（EGF）对人口腔鳞状细胞癌侵袭能力的影响，对5株细胞系进行了研究。EGF以剂量依赖性的方式增强了所有细胞系的随机运动性，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，为了揭示信号通路，我们建立了对EGF刺激最敏感的s-1克隆细胞和对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。

In order to clear the effects of Epidermal Growth Factor (EGF) on the invasion abilities of human oral squamous cell carcinoma, five cell lines were studied. EGF enhanced the random motility of all 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, we established s-1 clone cells, 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.