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研究生:邱文俞
研究生(外文):Wen-Yu Chiu
論文名稱:藤黃酸誘導人類口腔癌細胞凋亡的分子機制
論文名稱(外文):Molecular mechanism of gambogic acid-induced apoptosis in human oral cancer cells
指導教授:林巧雯林巧雯引用關係
指導教授(外文):Chiao-Wen Lin
口試委員:簡銘賢楊順發
口試委員(外文):Ming-Hsien ChienShun-Fa Yang
口試日期:2020-06-17
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:口腔科學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:78
中文關鍵詞:口腔癌藤黃酸細胞凋亡
外文關鍵詞:oral cancergambogic acidapoptosis
DOI:10.6834/csmu202000063
相關次數:
  • 被引用被引用:0
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  • 下載下載:7
  • 收藏至我的研究室書目清單書目收藏:0
口腔癌是常見的惡性腫瘤之一,其中以口腔鱗狀細胞癌最為常見。藤黃酸 (gambogic acid) 是從藤黃中分離出的天然成分,對多種類型的癌症均顯示出有效的抗癌活性。然而,藤黃酸在口腔癌中的作用仍不清楚。因此在本篇研究中,首先以細胞存活實驗觀察到藤黃酸顯著抑制口腔癌細胞生長。接著利用流式細胞儀觀察細胞週期的變化,觀察到sub-G1有增加的趨勢。更進一步使用Annexin V/PI雙重染色證實,藤黃酸誘導細胞凋亡比例增加。使用人類凋亡陣列實驗觀察到藤黃酸在SAS細胞中增加caspases-3及HO-1的表現,並降低cIAP1及XIAP的表現。在凋亡相關機制上,觀察到藤黃酸會活化caspase-8, caspase-9, caspase-3的表現及PARP裂解。藤黃酸透過活化MAPK的表現,並使用相關的抑制劑證實p38 MAPK訊息傳遞路徑來誘導細胞凋亡。總結以上結果表明,藤黃酸在口腔癌中是可以作為有效應用藥物,因此未來可以將藤黃酸作為口腔癌新的治療選擇。
Oral squamous cell carcinoma is the most prevalent oral cancer in the world. Gambogic acid, a natural component isolated from gamboge, has demonstrated potent anticancer activities in many types of cancers. However, the mechanisms of gambogic acid treatment in oral cancer remains unclear. In this study, we determined that gambogic acid can inhibit cell viability of oral cancer cells. Next, we analyzed the effect of gambogic acid on cell cycle in oral cancer cells and observed that the sub-G1 phase was increased. Furthermore, annexin-V/PI double staining revealed that gambogic acid induced an increased proportion of apoptotic cells. A human apoptosis array indicated that gambogic acid increased the expression of cleaved-caspases-3 and HO-1 and decreased the expression of cIAP1 and XIAP in SAS cells. In terms of apoptosis-related mechanisms, gambogic acid induced activated cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and cleaved PARP. Gambogic acid also induced cell apoptosis mediated by the activation of the phosphorylation p38 MAPK pathway, which was confirmed by using different inhibitors. In summary, these results indicate that gambogic acid can be used as an effective preventative agent in oral cancer and might represent a new treatment option.
中文摘要 V
Abstract VI
縮寫表 VII
壹、 緒論 1
一、 口腔癌 (Human oral cancer) 1
二、 藤黃酸 (Gambogic acid) 4
三、 細胞凋亡 (Apoptosis) 6
四、 細胞週期 (Cell cycle) 9
五、 訊息傳導路徑 (Signal Transduction Pathway) 10
六、 血紅素加氧酶 (Heme oxygenase-1, HO-1) 13
貳、 材料與方法 16
一、 實驗材料與配製方法 (Materials and methods) 16
二、 人類口腔癌細胞培養 (Oral cancer cells cell culture) 23
三、 藤黃酸 (gambogic acid,GA) 配製 25
四、 細胞存活率分析 (Analysis of cell viability) 25
五、 西方墨點法 (Western blot) 26
六、 流式細胞儀分析 (flow cytometry) 29
參、 實驗結果 32
一、 GA對於人類口腔癌細胞株 (SAS, SCC-9) 細胞存活之影響 32
二、 GA對於人類口腔癌細胞 (SAS, SCC-9) 細胞週期之影響 32
三、 GA對於人類口腔癌細胞 (SAS, SCC-9) 細胞凋亡之影響 33
四、 處理GA後對於人類口腔癌細胞 (SAS) 進行Human apoptosis array分析 33
五、 GA對於人類口腔癌細胞 (SAS, SCC-9) 細胞凋亡相關蛋白之影響 34
六、 GA對於人類口腔癌細胞 (SAS, SCC-9) 細胞凋亡路徑相關蛋白之影響 34
七、 GA對於人類口腔癌細胞 (SAS, SCC-9) MAPK路徑相關蛋白之影響 35
八、 GA與MAPK蛋白抑制劑對於人類口腔癌細胞 (SAS, SCC-9) 細胞凋亡相關蛋白之影響 35
肆、 討論 37
伍、 參考文獻 43
陸、 圖表與圖表說明 52
圖一、 GA對於人類口腔癌細胞株 (SAS, SCC-9) 細胞存活之影響 53
圖二、 GA對於人類口腔癌細胞 (SAS, SCC-9) 細胞週期之影響 55
圖三、 GA對於人類口腔癌細胞 (SAS, SCC-9) 細胞凋亡之影響 57
圖四、 處理GA後對於人類口腔癌細胞 (SAS) 進行Human apoptosis array分析 59
圖五、 GA對於人類口腔癌細胞 (SAS, SCC-9) 細胞凋亡相關蛋白之影響 61
圖六、 GA對於人類口腔癌細胞 (SAS) 細胞凋亡路徑之影響 63
圖七、 GA對於人類口腔癌細胞 (SCC-9) 細胞凋亡路徑之影響 65
圖八、 GA對於人類口腔癌細胞 (SAS) MAPK路徑相關蛋白之影響 67
圖九、 GA對於人類口腔癌細胞 (SCC-9) MAPK路徑相關蛋白之影響 69
圖十、 GA與MAPK蛋白抑制劑對於人類口腔癌細胞 (SAS) 細胞凋亡相關蛋白之影響 71
圖十一、 GA與MAPK蛋白抑制劑對於人類口腔癌細胞 (SCC-9) 之細胞凋亡相關蛋白之影響 73
圖十二、 GA誘導人類口腔癌細胞株 (SAS, SCC-9) 細胞凋亡之調控路徑圖 75
柒、 附錄 76
附錄一、 口腔癌TNM分期 76
附錄二、 人類細胞凋亡陣列 (Human apoptosis array) 78
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