2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644705摘要：頭頸癌為台灣男性主要癌症死因之ㄧ，近年來頭頸癌的治療雖有進步，但是疾病復發及轉移後產生之治療抗性，仍是頭頸癌治療主要障礙。結締組織生長因子(connective tissue growthfactor，簡稱 CTGF)為一種分泌型的蛋白質，目前已知參與了許多生物功能，如細胞分裂、細胞凋亡、細胞附著、細胞移動、細胞外基質製造與血管新生等，也常在許多不同的癌症中扮演不同的角色，然而其在頭頸癌細胞所扮演的角色目前仍不明。近年研究發現癌症幹細胞(cancer stem cells)與人類癌症復發與治療抗藥性有密切相關，且已成功從頭頸癌組織中分離出癌症幹細胞。我們初步的研究結果發現，頭頸癌細胞過度表現CTGF 或是外加CTGF 蛋白會使其幹細胞特性增加，且會增加幹細胞相關基因(stemness genes) Oct4，Nanog，Sox2之表現。而CTGF 促進幹細胞相關基因表現，可能與轉錄因子JUN 以及ESR2有關。本研究計畫目的在於驗證CTGF 是否會促進頭頸癌中幹細胞之特性，包括癌症幹細胞表面標記分析，活體外及活體內腫瘤生成實驗，細胞自我更新及分化實驗，都將用來確認CTGF 是否會促成頭頸癌細胞產生幹細胞特性。實驗設計亦將探討JUN 及ESR1 在頭頸癌細胞中調控Oct4，Nanog，Sox2 之分子機轉。另外，本研究計畫亦包括頭頸癌微環境之影響，探討CTGF 是否會經由癌細胞周圍之纖維母細胞(fibroblast)分泌來促成頭頸癌幹細胞生成。最後，我們將分析頭頸癌病患腫瘤組織，觀察CTGF 過度表現之臨床意義，以及 CTGF 表現量與幹細胞相關基因Oct4，Nanog，Sox2 之關連性。上述結果將對於CTGF在頭頸癌引發之癌症幹細胞生成之分子機轉及臨床意義，有重大且關鍵之貢獻，並且也將對於頭頸癌治療之未來發展提供重要的資訊。<br> Abstract: Head and neck squamous cell carcinoma (HNSCC) is one of the major cancers in Taiwan, especially for male. Tumor recurrence and drug resistance are still critical issues clinically. Connective tissue growth factor (CTGF) is a secreted cell matrix protein, which exhibits diverse cellular functions such as regulation of cell division, chemotaxis, apoptosis, adhesion, motility, and angiogenesis. CTGF is involved in the development and progression of different types of cancers. However, the role in HNSCC is still largely unknown. Cancer stem cells (CSC) have been shown to be critical in cancer progression, recurrence and treatment resistance, and successful isolation of CSC has been reported in HNSCC. In our preliminary study, we found that exogenous expression or recombinant CTGF protein treatment could enhance stemness property in HNSCC cells, and increase stemness gene (Oct4, Nanog, Sox2) expression. We also aim to investigate the molecular mechanism of how CTGF regulates the expression of stemness genes through the transcriptional factors, including ESR1 and JUN. The microenvironment of HNSCC will be considered in this project, we plan to elucidate whether CTGF secreted from fibroblasts around the tumor site could alter the stemness property in HNSCC. Finally, the clinical significance of CTGF expression will be established in clinical HNSCC samples, and its correlation with stemness genes in real-life samples will also be examined. We consider that if the speculation has been proved by conscientious study, application of CTGF treatment will be a possible future breakthrough for HNSCC therapy.結締組織生長因子間葉細胞－上皮細胞轉變幹細胞相關基因CTGF、MET、stemness gene