角蛋白是細胞中具有保持細胞型態、硬度的重要細胞骨架蛋白。近年來有研究指出角骨架纖維在癌症發展中佔有重要角色。在我們先前的研究中發現，咀嚼檳榔的口腔上皮細胞癌病人中，存在著K6與K14所形成的融合型基因。在本篇研究中，我們研究角蛋白融合的主要型態之一，並與較大的腫瘤有相關的K6-K14/V9，在癌症中所扮演的角色。我們使用四環素調控系統來控制目標基因在細胞中的表達。在K6-K14/V9基因表達後，細胞產生了主要分佈於細胞膜周圍，降低細胞膜上橋體的結構量，使細胞失去細胞間的附著力，並促進肌動蛋白相關得基因表達，肌動蛋白相關基因表達的提升促進了細胞的移動和侵犯能力。此研究揭露了角蛋白骨架在細胞中扮演的角色，此研究能夠提供我們在治療癌症上一個新的目標與想法。

Keratins are cytoskeleton proteins with major functions in controlling/maintaining cell morphology and stiffness. Recent studies indicated possible involvement of keratin filaments in cancer developments. In our previous study, we have identified the existence of keratin fusions between KRT6 and KRT14 genes in oral squamous cell carcinoma (OSCC), and patients with the history of chewing betel nut showed higher frequency to harbor such fusions in their tumor tissues. In this study, we studied bio-functional roles of a major keratin fusion isotype K6-K14/V9, which correlated with bigger tumor size, cell migration and invasion. We established a tet-off inducible gene expression system in OSCC cells. After gene being turned on, K6-K14/V9 formed a peripheral-dominant network with the loss of peri-nuclear arrays. Interestingly, the desmosome junction was found to be dramatically reduced, leading to loss of cell-cell contact, that subsequently up-regulated genes related actin filament activation via mechano-transduction. Actin-associated protrusion at cell leading edge was also increased by K6-K14/V9 to enhance cell migration and invasion. This study uncover new functions/definitions for keratin filament in cancer development, Mechanisms revealed in this study can help us to design new strategies for new drug development and clinical treatments.

目錄
Abstract iii
中文摘要 iv
前言 (Introduction) - 1 -
材料與方法 (Materials and Methods) - 6 -
討論 (Discussion) - 19 -
實驗成果 (Figures) - 22 -
參考文獻 (Reference) - 35 -

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