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

人口腔癌细胞中EGF刺激引起的细胞运动信号转导分析

• 批准号: 13672115
• 负责人: SHIBATA Tohiyuki
• 金额: $ 2.56万
• 依托单位: GIFU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672115/
• 关键词: HUMAN; SCC; ORAL CANCER; EGF; INVASION; MATASTASIS; METASTAIZS

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.

为探讨表皮生长因子（EGF）对人口腔鳞癌细胞侵袭能力的影响，对5株人口腔鳞癌细胞系进行了研究。EGF以剂量依赖性方式增强所有细胞系的随机运动性，并且暴露于EGF可以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。提示EGF可能促进口腔鳞癌的侵袭和转移。本研究建立了对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，以揭示EGF刺激的信号通路。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，随后通过erbB同源二聚体产生的PLCr的激活和/或erbB 3异源二聚体产生的PI 3-激酶的激活来激活PKC。此外，erbB同源二聚体通过激活PLC激活nPKCd，并且erbB/erbB-3异源二聚体也通过激活PI 3 K激活aPKCe。这些结果表明，抑制aPKCe或nPKCd可降低人口腔癌细胞的侵袭和转移，并可能建立起分子靶向药物研究的有用模型。

项目成果

T.Shibata, et al.-4: "Detection of TP53 mutation in ameloblastoma by the use of a yeast functional assay"J Oral Pathol Med. 31. 534-538 (2002)

T.Shibata 等人-4：“通过使用酵母功能测定法检测成釉细胞瘤中的 TP53 突变”J Oral Pathol Med。

Hamada, J., Nakata, D., Nakae, D., Kobayashi, Y., Akai, H., Konishi, Y., Okada, F., Shibata, T.et al.-2: "Increased oxidative DNA damage, 8-hydroxydeoxyguanosine, in rat ER-1 mammary tumor cells by continuous EGF-stimulation"J. Natl. Cancer Inst. 93. 214-

Hamada, J.、Nakata, D.、Nakae, D.、Kobayashi, Y.、Akai, H.、Konishi, Y.、Okada, F.、Shibata, T.et al.-2：“氧化 DNA 损伤增加

J.Hamada, D.Nakata, T.Shibata et al.: "Increased Oxidative DNA Damage in Mammary Tumor Cells by Continuous Epidermal Growth Factor Stimulation"Journal of the National Cancer Institute. 93. 214-216 (2001)

J.Hamada、D.Nakata、T.Shibata 等人：“通过连续表皮生长因子刺激增加乳腺肿瘤细胞的氧化性 DNA 损伤”美国国家癌症研究所杂志。

T. Kobayashi, F. Okuda, N. Fuji, N. Tomita, S. Ito, H, Tazawa, T. Aoyama, Sung Ki Choi, T. Shibata, et al.-3: "Thymosin-β 4 Regulates Motility and Metastasis of Malignant Monse Fibrosarcoma Cells"American J. of Pathology. 160, (3). 869-875 (2002)

T. Kobayashi、F. Okuda、N. Fuji、N. Tomita、S. Ito、H、Tazawa、T. Aoyama、Sung Ki Choi、T. Shibata 等人-3：“胸腺素-β 4 调节运动和恶性蒙斯纤维肉瘤细胞的转移”American J. of Pathology. 160, (3). 869-875 (2002)

Zeki Topcu, I.Chiba, M.Fujieda, T.Shibata, et al.-7: "CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka"Carcinogenesis. 23. 595-598 (2002)

Zeki Topcu、I.Chiba、M.Fujieda、T.Shibata 等人-7：“CYP2A6 基因缺失降低了斯里兰卡嚼槟榔者的口腔癌风险”致癌作用。