口腔黏膜下纖維化症 (oral submucous fibrosis)為一種口腔癌發生之癌前病變 (precancerous condition)，流行病學指出口腔黏膜下纖維化症主要與檳榔嚼食習慣相關， 檳榔中的主要成分檳榔素(arecoline)對於口腔黏膜下纖維化症所造成的病理病灶已經被 確立，然而口腔黏膜纖維化症之分子致病機轉至今仍尚未清楚有待進一步研究探討。微 小RNA (microRNAs)是一類長度約19-24個核苷酸之non-coding RNA，可利用鹼基配對的 方式與標靶mRNA的3’UTR (untranslation region)結合而抑制mRNA的轉譯，許多證據亦 顯示微小RNA在組織纖維化中扮演重要角色，但微小RNA於口腔黏膜下纖維化症之角色 仍未知，因此本計畫目的欲了解微小RNA對於口腔黏膜下纖維化症之影響，希望能對口 腔黏膜下纖維化症病理機轉了解有所助益。本研究計劃的具體目標包含：(1) 探討微小 RNA在正常頰黏膜及口腔黏膜下纖維化症之組織病理意義; (2) 在正常頰黏膜造纖維母 細胞處理不同濃度檳榔素後微小RNA表現變化; (3) 口腔黏膜下纖維化症之造纖維母細 胞過度表現抗纖維化(anti-fibrotic)對纖維化表型之變異; (4) 口腔黏膜下纖維化症造纖維 母細胞抑制促纖維化(pro-fibrotic)對纖維化表型之影響; (5) 研究口腔黏膜下纖維化症相 關微小RNA之下游標的基因以瞭解其生物功能; (6) 微小RNA參與口腔黏膜下纖維化症 造纖維母細胞轉分化及上皮間質轉換過程之機制研究;本研究成果能了解微小RNA在口 腔黏膜下纖維症之致病機轉及訊號傳遞路徑，且希望利用微小RNA作為口腔黏膜下纖維 化症治療標靶並且作為之診斷標記，提供疾病防治之新視野。 Oral submucous fibrosis (OSF) is a chronic progressive scarring disease which has been considered as pre-cancerous condition of oral mucosa. OSF is highly associated with areca quid chewing habit. Arecoline is the major alkaloid in areca quid which has been suggested to be involved in the pathogenesis of OSF. However, the pathologic mechanisms of OSF still need to be further clarified. In the past decade, the biological function and biogenesis of microRNAs (miRNAs) became popular topics for biomedical researches. Analyses of these miRNAs in mechanistic studies are crucial to better understanding of fibotic diseases and with the aim to eventually identify novel therapeutic targets. The purpose of this study is to investigate the roles of miRNAs in the pathogenesis of OSF. The specific aims of this proposal are: (1) Exploration of the specifically expressed miRNAs in OSF; (2) Examination of the expression of miRNAs of normal buccal mucosa fibroblasts treatment with different concentrations arecoline; (3) Investigation of the effect of overexpression of anti-fibrotic miRNAs on fibrotic phenotypes in OSF; (4) Examination of the effect of down-regulation of pro-fibrotic miRNAs on fibrotic phenotypes in OSF ; (5) Search and study of the mechanisms of miRNAs and their downstream genes related to OSF; (6) Involvement of miRNAs in myofibrobalst transdifferentiation or epithelial-mesenchymal transition in OSF. The results generated in this study may offer an insight into the areca nut-associated miRNAs regulating profibrotic pathways and extracellular matrix synthesis in OSF. This study will open a new avenue for miRNAs research on pre-cancer disease and lead to the rational design and the development of innovative methods for the prevention of OSF.
