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系統識別號 U0002-1307201423470600
中文論文名稱 氧化鋅奈米粒子誘導人類口腔癌細胞凋亡機轉之研究
英文論文名稱 ZnO nanoparticles-induced Apoptotic Mechanism in Human Oral Squamous Cancer Cell
校院名稱 淡江大學
系所名稱(中) 水資源及環境工程學系碩士班
系所名稱(英) Department of Water Resources and Environmental Engineering
學年度 102
學期 2
出版年 103
研究生中文姓名 林民生
研究生英文姓名 Ming-Shen Lin
學號 600480601
學位類別 碩士
語文別 中文
口試日期 2014-06-06
論文頁數 77頁
口試委員 指導教授-陳俊成
委員-陳俊成
委員-申永順
委員-王士維
中文關鍵字 氧化鋅  口腔癌細胞  細胞凋亡  活性氧化物質  粒線體膜電位  抗氧化酵素  細胞週期 
英文關鍵字 Zinc oxide  oral cancer cells  apoptosis  ROS  mitochondrial membrane potential  Antioxidant enzymes  Cell cycle 
學科別分類 學科別應用科學環境工程
中文摘要 氧化鋅奈米粒子 (ZnO-NPs) 應用在防曬乳、食品添加、顏料、橡膠製造和電子材料上已日益增加。許多研究顯示ZnO-NPs可在多種人類癌細胞中會藉由產生氧化壓力抑制細胞生長,並且誘導細胞凋亡。然而,有關於ZnO-NPs在人類口腔癌細胞中的抗癌作用及分子機制尚未有清楚的研究。在本研究中,我們發現ZnO-NPs會抑制人類口腔鱗狀細胞癌Ca9-22細胞的生長,並呈濃度相關性誘發細胞凋亡。利用流式細胞儀分析細胞週期的變化,發現ZnO-NPs 可明顯地增加細胞sub-G1階段的累積。更重要的是我們發現ZnO-NPs不會損害正常細胞的存活率,如人類角質細胞 (HaCaT),此結果顯示 ZnO-NPs可以選擇性在人類口腔鱗狀癌細胞產生細胞毒性。此外,ZnO-NPs 會誘導超氧化物的產生,並造成粒線體膜電位的喪失。抗氧化物殼胱甘肽 (GSH) 的前驅物 N-乙酰半胱胺酸(NAC) 會減少 ZnO-NPs 誘發的細胞死亡及超氧化物的生成。在西方點墨法的實驗則發現ZnO-NPs 會誘導caspase-3、caspase-7、caspase-9 及 PARP 的裂解,此結果顯示ZnO-NPs可經由caspase cascade誘發細胞凋亡。但是,ZnO-NPs 並沒有抑制pro-Bcl-2家族及抗氧化酶的蛋白表現。ZnO-NPs 也不影響 MAPKs激素,包括ERK1/2、JNK及p38的磷酸化。這些結果顯示,pro-Bcl-2家族及抗氧化酶的調控,以及MAPKs的訊息傳遞路徑,不會參與 ZnO-NPs 誘導細胞凋亡的過程。綜合以上結果,我們證明 ZnO-NPs 可能經由誘發超氧化物的生成以及粒線體的破壞,造成 caspase cascade的活化,最後促使人類口腔鱗狀癌細胞走向細胞凋亡。因此,我們認為ZnO-NPs 是一種具有潛力的抗癌物質,值得進行後續的藥物研發,應用於人類口腔鱗狀細胞癌的治療。
英文摘要 Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, food additives, pigments, rubber manufacture, and electronic materials. Several studies have shown that ZnO-NPs inhibits cell growth and induces apoptosis by the production of oxidative stress in a variety of human cancer cells. However, the anti-cancer effect and molecular mechanism of ZnO-NPs in human oral cancer cells are not fully understood. In this study, we found that ZnO-NPs induced growth inhibition of human oral squamous cell carcinoma (OSCC) Ca9-22 cells. ZnO-NPs caused apoptotic cell death of Ca9-22 cells in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation. Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs in Ca9-22 cells. Importantly, ZnO-NPs did not impair the viability of normal cell types, like human keratinocytes (HaCaT cells), indicating ZnO-NPs may exerts the selective cytotoxicity in human OSCC cells.Furthermore, ZnO-NPs induced the generation of superoxide and loss of mitochondrial membrane potential. The antioxidant and glutathione precursor N-acetylcysteine significantly abolished ZnO-NPs-induced cell death and superoxide production. In addition, the immunoblotting assays showed that ZnO-NPs induced the activation of caspase-3, -7, and -9 and the cleavage of poly (ADP-ribose) polymerase, indicating the involvement of caspase-dependent cascade. However, ZnO-NPs did not inhibit the protein expression of pro-survival Bcl-2 family and antioxidant enzymes. ZnO-NPs also did not affect the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK, and p38. These results suggest that modulation of pro-survival Bcl-2 family and antioxidant enzymes as well as MAPKs signaling pathways are not involved in ZnO-NPs-induced apoptosis. Taken together, we demonstrate that ZnO-NPs may cause superoxide generation and mitochondrial disruption, leading to activation of caspase cascade, and subsequently apoptotic cell death in human OSCC cells. Therefore, ZnO-NPs is a potential anti-cancer agent worthy of further development for treatment of human OSCC.
論文目次 目錄
圖目錄 IV
表目錄 VI
第一章 前言 1
1-1 研究起源 1
1-2 研究目的 2
1-3 研究內容 3
第二章 文獻回顧 4
2-1 口腔癌 4
2-1-1 口腔癌之成因及特色 4
2-1-2 口腔癌之治療方式 5
2-2 光催化反應原理 8
2-2-1 半導體特性 8
2-2-2 光催化機制 9
2-3氧化鋅之特性與應用 14
2-3-1 氧化鋅晶形與結構 14
2-3-2 氧化鋅之應用 15
2-3-3 影響氧化鋅光催化反應之因素 16
2-3-4 氧化鋅奈米粒子相關的抗癌研究 18
2-4細胞凋亡(Apoptosis) 20
2-4-1細胞死亡的種類 20
2-4-2 ROS與細胞凋亡 21
2-4-3 粒線體與細胞凋亡 24
2-4-4 Caspase family與細胞凋亡 25
2-4-5 MAPK與細胞凋亡 27
2-4-6 細胞週期與細胞凋亡 28
第三章 實驗材料與方法 31
3-1 實驗儀器 31
3-2 實驗藥品及藥品配製 32
3-2-1 實驗藥品 32
3-2-2 Dulbecco’s Modified Eagle’s Medium (DMEM)培養基配製 33
3-2-3 Phosphate Buffered Saline (PBS) 配製 33
3-3 細胞株培養(Cell Culture) 34
3-4 MTT Assay 細胞存活率分析方法 37
3-5 Cell Death Detection ELISA 39
3-6 Reactive oxygen Species (ROS) 的測定 41
3-7 粒線體膜電位(△Ψm)的測定 42
3-8 西方墨點法-細胞蛋白質測定 43
3-8-1細胞內蛋白質分離 43
3-8-2蛋白質(protein)定量 43
3-8-3西方墨點法 (Western Blot) 44
3-9 利用Flow cytometry測定細胞週期變化 47
3-10 統計方法 47
第四章 實驗結果 48
4-1氧化鋅奈米粒子之光催化反應對人類口腔癌細胞生長之影響 48
4-2 改質TiO2-NPs對人類口腔癌細胞生長之影響 49
4-4 氧化鋅奈米粒子對其他人類癌細胞生長之影響 53
4-5 氧化鋅奈米粒子對人類正常角質細胞生長之影響 54
4-6 氧化鋅奈米粒子對人類口腔癌細胞凋亡之影響 55
4-7 氧化鋅奈米粒子刺激Reactive oxygen species (ROS)產生 56
4-8 氧化鋅奈米粒子對人類口腔癌細胞粒腺體膜電位之影響 58
4-9 氧化鋅奈米粒子對 Caspase family 之影響 59
4-10 氧化鋅奈米粒子對 Bcl-2 family 之影響 61
4-11 氧化鋅奈米粒子對 MAPK pathway 之影響 63
4-12 氧化鋅奈米粒子對 Antioxidant enzymes 之影響 64
4-13 氧化鋅奈米粒子對人類口腔癌細胞細胞週期之影響 65
第五章 結論與建議 67
5-1 結論 67
5-2 建議 70

圖目錄
圖 2 1光催化機制圖 10
圖 2-2 光觸媒圖解 11
圖 2-3常見之半導體之能隙分布圖 13
圖 2-4氧化鋅纖鋅礦結構 14
圖 2-5活性氧化物質(ROS)的生成及清除路徑 22
圖 2-6 NAC促進GSH生成路徑 23
圖 2-7 Bcl-2 family 之細胞凋亡路徑 25
圖 2-8 Caspase family 之細胞凋亡路徑 27
圖 2-9 細胞週期示意圖 30
圖 3-1 細胞計數盤 36
圖 3-2 MTT結構圖 37
圖 3-4 CDD 反應過程 39_Toc390720050
圖 4-1 低濃度氧化鋅奈米粒子之光催化反應對人類口腔癌細胞之影響 48
圖 4-2 改質二氧化鈦不同濃度及不同照射時間對Ca9-22細胞生長之影響 50
圖 4-3 氧化鋅奈米粒子對人類口腔癌細胞生長之影響 52
圖 4-3 氧化鋅對不同株細胞生長之影響 54
圖 4-5氧化鋅奈米粒子對人類正常角質細胞生長之影響 54
圖 4-6 氧化鋅誘導口腔癌細胞Ca9-22造成細胞凋亡 55
圖 4-7 氧化鋅奈米粒子刺激 ROS 及 Superoxide 的產生。 57
圖 4-8抗氧化劑 NAC 對氧化鋅奈米粒子抑制口腔癌細胞生長之影響 57
圖 4-9氧化鋅奈米粒子對人類口腔癌細胞粒腺體膜電位之影響 58
圖 4-10 氧化鋅奈米粒子對 Caspase family 之影響 60
圖 4-11 氧化鋅奈米粒子對 Bcl-2 family 之影響 62
圖 4-12 氧化鋅奈米粒子對MAPK pathway 之影響 63
圖 4-13 氧化鋅奈米粒子對 Antioxidant enzymes 之影響 64
圖 4-14 流式細胞儀分析 65
圖 5-1 ZnO-NPS 誘導Ca9-22凋亡可能之路徑圖 71

表目錄
表 2-1半導體之能隙寬度及光激發所需光波波長 12
表 2-2 ZnO基本物理性質 15
表 3-1 實驗儀器 31
表 3-2 實驗藥品 32
表3-3 PBS配方表 33
表3-4 SDS-PAGE 配方表 45
表4-1 改質二氧化鈦對乙烯之去除率 50
表4-2 以不同濃度之 ZnO-NPs 處理 Ca9-22 細胞,對細胞週期所造成的影響 66
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