臺灣博碩士論文加值系統

根據近年衛生福利部的癌症流病調查，口腔癌為台灣癌症發生率第六名的癌症，其死亡率更高達第五名。Clioquinol (CQ)是一金屬螯合劑，可與鋅、鐵、銅等二價金屬離子結合。早期CQ用於口服治療阿米巴原蟲引起的腸道感染，亦作為抗菌藥物使用。然而，近年來有研究指出CQ具有抗癌潛力。CQ藉由金屬螯合特性，調節腫瘤周邊所累積的銅離子，進而促使細胞凋亡。為了解CQ螯合銅離子在口腔癌上的抗癌機制，本研究利用液相層析串聯質譜，分析口腔癌細胞受CQ與銅離子刺激後，蛋白質表現的變化。經由多項實驗驗證，證實CQ與銅離子合併刺激口腔癌細胞株HSC-3，會促使凋亡誘發因子AIF自粒腺體內膜轉位至細胞核中，進而在細胞核內造成DNA受損，引發Caspase非依賴性細胞凋亡。同時，CQ與銅離子合併刺激會藉由抑制Cyclin A2、Cyclin B1、Cyclin B2、CDC25B等G2/M期轉換調控因子的mRNA或蛋白質表現，提升p21蛋白表現量，進而降低CDK1的活性，使HSC-3細胞生長週期停滯於G2期，阻斷細胞週期的運行，達到抑制口腔癌細胞生長的作用。

According to cancer epidemiology report from Ministry of Health and Welfare, oral squamous cell carcinoma (OSCC) is the sixth of cancer incidence and the fifth of cancer mortality in Taiwan. Clioquinol (CQ) is the metal chelator which binds to divalent ion, such as zinc, iron, copper and so on. CQ was used as an antiseptic and oral intestinal amebicide in the past. However, CQ has been notified by its anticancer function nowadays. By acting as chelator and/or ionophore, CQ regulates the copper ion, which is specifically accumulated around the tumor site, to induce cell apoptosis. It has been reported that the concentration of copper in saliva and serum is relatively higher in OSCC patients than in healthy people. To decipher the underlying mechanisms of how CQ-copper exerts the anti-cancer function in oral cancer cells, liquid chromatography-tandem mass spectrometry was used for analyzing the differences on proteins between the DMSO-treated oral cancer cells and the CQ-copper-treated group. The present data demonstrated that CQ-copper combined treatment could cause Apoptosis Inducing Factor translocate from mitochondria inner-membrane to nuclear, then further damage DNA in a Caspase-3-independent action in HSC-3 cells. Meanwhile, CQ-copper combined treatment could also induce G2 arrest through regulating several G2/M phase transition regulators. The decrease of Cyclin A2, Cyclin B1, Cyclin B2, CDC25B, and the induction of p21 led to the consequent suppression of CDK1 activity. Taken together, CQ exerts the anti-cancer effects via induction of apoptosis and cell cycle arrest simultaneously in oral cancer cells.

目錄
中文摘要 I
英文摘要 II
致謝 III
1.背景介紹 1
1.1 口腔癌流行病學 1
1.2 口腔癌致癌因子 2
1.3 口腔癌致病機轉 3
1.4 口腔癌臨床治療 4
1.5 金屬銅離子 6
1.6 Clioquinol藥物介紹 7
1.7 Apoptosis inducing factor (AIF) 10
1.8 細胞週期G2/M的轉換 11
1.9 研究動機 12
2.材料與方法 14
2.1 細胞培養 14
2.2 液相層析串聯質譜分析 14
2.3 即時偵測聚合酶連鎖反應 (Real-Time PCR) 16
2.4 西方墨點法 17
2.5 細胞生長週期分析 19
2.6 細胞即時影像分析 20
2.7 螢光免疫染色法 20
3.結果 21
3.1 液相層析串聯式質譜分析分別於實驗組和對照組偵測出Caspase非依賴性之細胞凋亡調節蛋白—AIF和細胞週期G2/M轉換調控蛋白—Cyclin B2。 21
3.2 AIF蛋白轉位至細胞核進行染色體濃縮、DNA裂解，為CQ與Cu2+引發HSC-3細胞凋亡的路徑之一。 22
3.3 CQ與Cu2+合併刺激抑制HSC-3的Cyclin B2蛋白和mRNA表現。 23
3.4 CQ與Cu2+合併刺激造成HSC-3生長週期停滯於G2期。 24
3.5 CQ與Cu2+合併刺激降低HSC-3細胞週期調控相關因子—p53、Cyclin A2、CDC25B的mRNA表現。 25
3.6 CQ與Cu2+合併刺激藉由調控CDK1蛋白活性，使HSC-3生長週期停滯於G2期。 26
4.討論 29
5.結論 34
6.參考資料 35
7.附錄 45

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