口腔黏膜纖維化(oral submucous fibrosis)為一種口腔癌發生之癌前病變，主要與檳 榔嚼食習慣相關，然而口腔黏膜纖維化症之致病分子機轉尚未清楚。癌症幹細胞被認為 對口腔癌腫瘤的進展、轉移、及復發扮演相當重要的角色。近年來，癌幹細胞特性的也 存在對於皮膚良性腫瘤蟹足腫(keloid)中，因此本計畫目的欲了解幹細胞特性對於癌前病 變口腔黏膜纖維化之影響，希望能對口腔黏膜纖維化症病理機轉了解有所助益。 本研究團隊過去對於口腔黏膜纖維化症及口腔癌幹細胞鑑定與功能性分析已有成 果，然而幹細胞特性對於口腔黏膜下纖維角色及致病分子機轉仍未知。本研究計畫目的 主要將探討在幹細胞特性在口腔黏膜下纖維的功能。進一步了解幹細胞基因經由何種重 要途徑如：上皮- 間質細胞轉換過程(Epithelial-mesenchymal transition) 、細胞激素 (Cytokine network)或基質金屬蛋白水解?(Matrix metalloproteinases)相關分子訊號來維 持口腔癌幹細胞之特性而影響的口腔黏膜下纖維化發生。 本研究計劃的具體目標包含：(1)臨床上探討幹細胞基因表現在正常頰黏膜及口腔黏 膜下纖維化母組織之病理意義; (2)分離出口腔黏膜下纖維化母組織幹細胞及鑑定其特性; (3)在正常頰黏膜纖維母細胞在處理不同arecoline 處理下幹細胞特性的表現; (4)在正常 頰黏膜纖維母細胞在處理不同arecoline 處理下幹細胞gene 的表現; (5)進一步利用干擾 性核醣核酸(RNAi)及系統生物學技術探討來幹細胞基因對於口腔黏膜下纖維化母細胞 之訊息傳導。本研究成果能了解幹細胞特性在口腔黏膜下纖維之致病機轉及訊號傳遞路 徑，且希望利用幹細胞特性當作口腔黏膜下纖維化治療標靶並且作為之診斷標記。 Oral submucous fibrosis (OSF) is regarded as a precancerous condition, and is a chronic insidious disease of oral subepithelial connective tissue. The role of the constituents of areca nut in the pathogenesis of OSF has been studied. But, the pathologic mechanism(s) of OSF needs to be further clarified. Accumulating data support the hierarchical model of cancer stem cells (CSCs) such that each tumor formation is governed by a rare subpopulation of cells with self-renewal capacity. CSCs have been demonstrated to have capacities of promoting tumor growth, tumor regeneration, metastatic progression and contributing to radio-resistance and chemo-resistance. Recently, the CSCs properties also examined in benign tumor keloid. The purpose of this study is to investigate the stemness in the maintenance pathogenesis of OSF. The specific aims of this proposal are: (1) Clinical significance of stemness markers in OSF specimens; (2) Isolation and characterization of OSF-derived putative stem cells; (3) Examination of the effect of stemness properties of normal buccal mucosa fibroblast (BMF) after different concentration arecoline treatment; (4) Examination of the effect of stemness properties of BMF after different concentrations arecoline treatment; (5) Characterization the detailed molecular mechanisms by which stemness markers mediating the pathogenesis of OSF by siRNA and systemic biology. In three years, we expect to provide the crucial role stemness properties of in the maintenance of OSF.
