臺灣博碩士論文加值系統

　　口腔癌為常見的癌症。在臺灣，2018年的口腔癌死亡率為癌症死亡率排名中的第五名。雖然手術治療為口腔癌主要的治療方式，但對於不適合手術治療及晚期的口腔癌，化學治療仍是重要的治療方式。目前晚期的口腔癌預後仍是不佳的，因此找尋更有效治療口腔癌之方法是重要的。
　　綜合壓力反應 (ISR)是細胞遭受壓力時所產生的反應，主要的核心是磷酸化eIF2α。當細胞處於缺氧、胺基酸缺乏、病毒感染及內質網壓力時，會造成eIF2α激酶的活化，使eIF2α磷酸化而啟動綜合壓力反應，造成細胞蛋白合成受到抑制，然而，ATF4蛋白的轉譯會被活化。ATF4為一種轉錄因子，能夠促進下游基因表現。活化綜合壓力反應能夠促進細胞的生存，但細胞長期處於綜合壓力反應之下則會造成細胞的死亡。在此研究中，利用NHOK、OECM-1及三種不同特性的SAS細胞株，包括低致瘤性細胞SAS-P、高致瘤性細胞SAS-VO3及易轉移細胞SAS-M5進行實驗。本篇研究發現利用salubrinal活化綜合壓力反應會抑制細胞生長、形成群落能力、形成sphere能力及移動能力，但會造成細胞產生抗藥性。此外，活化綜合壓力反應會造成細胞呼吸下降，增加細胞內及粒線體內活性氧分子的含量，粒線體質量也有增加的情況。然而，活化綜合壓力反應會減少粒線體DNA拷貝數，但不會影響粒線體基因及蛋白表現量。在代謝方面，活化綜合壓力反應會降低細胞呼吸速率，而細胞葡萄糖的攝取量沒有增加，會使細胞處於缺乏能量的情形，且會增加細胞對於葡萄糖的依賴性。
　　此研究說明在口腔癌細胞中活化綜合壓力反應能夠抑制口腔癌細胞惡性特性及降低粒線體呼吸功能和改變細胞代謝。因此，綜合壓力反應的活化，未來可能可以做為一個癌症治療的方式，達到增加病患存活率的效果。

　　Oral cancer is the common cancers. In Taiwan, the mortality rate of oral cancer in 2018 was ranking five. Although the main treatment for oral cancer is surgical treatment, chemotherapy is still important treatment for unfit for surgery and advanced oral cancer. Patients with advanced oral cancer are still poor prognosis, so it is of crucial importance to find a more effective treatment for oral cancer.
　　Integrated stress response (ISR) is a response to stress stimuli and the core event of ISR is phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α). When cells are under hypoxia, amino acid deprivation, viral infection, or endoplasmic reticulum stress, eIF2α kinase would be activated and phosphorylate, which activates stress response. Active ISR represses global protein synthesis but induces translation of the transcription factor 4 (ATF4). ATF4 is a transcription factor which can regulate its downstream genes. Activation of ISR would promote cell survival, but a prolonged activation of ISR would induce cell death. In this study, it was investigated that the role of ISR in NHOK, OECM-1 and three types of SAS cell lines including a low tumorigenic oral cancer cells (SAS-P), a high tumorigenic oral cancer cells (SAS-VO3) and a more metastatic oral cancer cells (SAS-M5). The data revealed that salubrinal-induced ISR represses cell growth, colony formation, sphere formation and migration, but enhances drug resistance. In addition, active ISR repressed respiration rates and increased cellular and mitochondrial ROS levels, and increased mitochondrial mass. However, active ISR decreased mitochondrial DNA copy number but not changed mitochondrial gene and protein level expressions. In the aspect of metabolism, active ISR decreased respiration rates and did not increase glucose uptake, which caused energy stress. Active ISR also increased glucose dependence.
　　These findings obtained from this study indicated that active ISR could repress cancer cell malignant phenotypes, mitochondrial function and change metabolism in oral cancer cells. These findings suggested that activating ISR can be a potential treatment strategy for oral cancer patients to increase patient survival rates.

目錄
致謝.................................................................i
中文摘要............................................................ii
英文摘要 ..........................................................iii
目 錄..............................................................v
圖目錄.............................................................vi
表目錄............................................................vii
縮寫表...........................................................viii
研究背景............................................................1
研究目的............................................................7
實驗設計............................................................8
材料與方法.........................................................10
結果..............................................................21
討論..............................................................29
結論..............................................................33
參考資料..........................................................34
圖表..............................................................41
表................................................................62
附錄..............................................................63

圖目錄
圖一、以salubrinal活化綜合壓力反應.................................41
圖二、活化綜合壓力反應抑制口腔癌細胞生長............................42
圖三、活化綜合壓力反應抑制口腔癌細胞結球能力........................44
圖四、活化綜合壓力反應抑制口腔癌細胞形成群落能力....................45
圖五、活化綜合壓力反應抑制口腔癌細胞在軟瓊脂膠中形成的群落數.........46
圖六、活化綜合壓力反應抑制口腔癌細胞移動能力........................48
圖七、活化綜合壓力反應增加口腔癌細胞的抗藥性........................50
圖八、活化綜合壓力反應稍微增加細胞內及粒線體內ROS的含量..............51
圖九、活化綜合壓力反應，增加粒線體質量..............................52
圖十、活化綜合壓力反應降低粒線體DNA copy number.....................53
圖十一、活化綜合壓力反應對於粒線體基因及蛋白質的影響.................54
圖十二、活化綜合壓力反應造成細胞呼吸下降可能和抑制mTOR路徑相關........55
圖十三、活化綜合壓力反應對於葡萄糖攝取及乳酸的影響...................56
圖十四、處理oligomycin活化綜合壓力反應對於葡萄糖攝取及乳酸的影響.....57
圖十五、活化綜合壓力反應可活化AMPK路徑..............................58
圖十六、活化綜合壓力反應改變細胞對葡萄糖的依賴性.....................59
圖十七、總結示意圖.................................................61

表目錄
表格1、Real-time PCR 引子序列表....................................62

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