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研究生:張順閔
論文名稱:探討EB病毒核抗原衍生蛋白與17-AAG壓制神經膠原致癌基因所介導的卵巢癌細胞轉型之協同作用
論文名稱(外文):To investigate the synergistic effects of EBNA1-derived polypeptide and 17-AAG suppress HER2/neu mediated cell transformation in HER2-overexpressing ovarian cancer cells
指導教授:蔡宗杰蔡宗杰引用關係
學位類別:碩士
校院名稱:國立嘉義大學
系所名稱:微生物免疫與生物藥學系研究所
學門:生命科學學門
學類:其他生命科學學類
論文種類:學術論文
畢業學年度:103
語文別:中文
中文關鍵詞:卵巢癌神經膠原致癌基因熱休克蛋白九十熱休克蛋白九十抑制劑細胞轉型作用EB病毒核抗原
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在臺灣卵巢癌是常見的女性的癌症之一,每年約有2-3千的婦女死於卵巢癌,其中約有20-30%的卵巢癌病人有神經膠原致癌基因 (HER2/neu) 過度表現。過度表現HER2/neu的卵巢癌具有高度侵犯性,對化療藥物產生抗性以及造成預後不良,因此以HER2/neu作為治療的標的或許可以降低腫瘤對化療藥物的抗性。熱休克蛋白九十 (heat shock protein90, HSP90) 是ㄧ種伴顧蛋白 (chaperone protein) 可以將受到壓力而變性的蛋白進行重新的折疊使其恢復正常的功能,或是將新合成尚未具有功能性的蛋白進行折疊使其有功能性。受到HSP90調控的蛋白分子很多,而這些蛋白都可以調控細胞的生長並且具有致癌的潛力,如果這些蛋白失去調控、過度表現或是高度活化都會導致腫瘤的生成,而HER2就是受到HSP90調控的蛋白之一。近年來有一類針對HSP90的抑制劑被開發出來,17-Demethoxy-17-allyaminogeldanmycin (17-AAG) 就是屬於這一類的藥物。17-AAG會競爭HSP90的ATP活化位, 讓HSP90的受顧蛋白 (client protein) 無法進行正確的折疊而造成蛋白被降解。
先前的研究指出Epstein-Barr病毒核抗原 (EBNA1) 會在轉錄的階層抑制HER2/neu基因的表現,提升癌細胞對化療藥物的敏感性。為增加EBNA1蛋白在過度表現HER2/neu癌症治療的臨床應用性,本實驗室先前分析發現另一EBNA1的衍生蛋白 (ΔG/A) 相較於野生型EBNA1其抑制HER2/neu的能力較佳。因此,本實驗擬結合ΔG/A和17-AAG,單獨或合併處理評估對於卵巢癌細胞的生長、轉型的抑制效果。首先利用先前實驗室所建立的人類卵巢癌細胞株SKOV3-Neo (控制組) 和SKOV3-ΔG/A (實驗組) 並利用細胞存活率檢測試劑進行細胞的存活率測試,評估不同濃度的17-AAG以及不同的時間點對細胞的影響。發現合併處理ΔG/A和17-AAG相較於單獨處理17-AAG對細胞的存活有顯著的抑制情形。接著利用西方墨點法來分析HER2蛋白是否會受到影響,從結果中我們看到ΔG/A結合17-AAG相較於單獨處理17-AAG對HER2蛋白有非常顯著的抑制效果。之後我們以適當濃度的17-AAG處理細胞後用軟瓊脂膠 (soft agarose assay) 分析細胞受到17-AAG單獨處理或是合併ΔG/A處理是否會改變細胞轉型能力,在結果中看到SKOV3-ΔG/A細胞未經前處理17-AAG本身就具有抑制細胞轉型的能力,而經過藥物處理後抑制的效果更加的明顯。透過ΔG/A加上17-AAG的處理模式下對於HER2過度表現的卵巢癌細胞有非常好的抑制效果,不論是細胞存活率、HER2的表現、和細胞轉型能力都受到極大程度上的協同抑制。因此,本論文的研究結果可以提供未來治療過度表現HER2的卵巢癌病患的治療策略之一。
中文摘要 I
英文摘要 III
誌 謝 V
目錄 1
圖目錄 4
縮寫表 5
第一章、緒論 7
第一節、人類神經膠原致癌基因 (HER2/neu) 在癌症中的角色 7
壹、HER2蛋白結構 7
貳、HER2蛋白訊息傳遞 8
叁、HER2與癌症的關連 9
肆、以HER2當作癌症治療的標的策略 10
壹、HSP90對細胞生理功能的作用 16
貳、HSP90與癌症的關係 17
叁、17-AAG抑制HSP90的功能 17
第三節、EB病毒核抗原一型 (EBNA1) 作為癌症治療藥物的潛力 19
壹、EBNA1原本功能與抑制HER2蛋白表現 19
第四節、研究目的及動機 21
第五節、實驗方法 23
第二章、材料與方法 24
第一節、實驗材料 24
壹、細胞株 24
貳、抗體 24
叁、化學試劑藥品 24
肆、實驗儀器 26
第二節、實驗方法 27
壹、卵巢癌細胞株培養及繼代培養 27
貳、細胞藥物處理 27
叁、製備細胞蛋白 28
肆、蛋白質定量 29
伍、SDS-PAGE蛋白質電泳 30
陸、西方墨點法 32
柒、細胞計數 33
捌、細胞活性檢測 34
玖、軟膠瓊脂分析細胞轉型能力 34
壹拾、利用Image J影像分析軟體定量壓片結果 36
壹拾壹、藥物半數抑制濃度 (IC50) 計算 36
壹拾貳、資料統計分析方法 37
第三章、結果 38
第一節、分析EBNA1衍生蛋白 (ΔG/A) 抑制卵巢癌細胞HER2蛋白表現與細胞生長 38
壹、利用西方墨點法和細胞存活率檢測試劑分析SKOV3-Neo和SKOV3-ΔG/A卵巢癌細胞生長和HER2的表現 38
第二節、17-AAG抑制SKOV3-Neo和SKOV3-ΔG/A卵巢癌細胞的生長速率以及HER2蛋白的表現 39
壹、利用細胞存活率檢測試劑分析SKOV3-Neo和SKOV3-ΔG/A卵巢癌細胞經過17-AAG處理後的細胞生長速率 39
貳、利用西方墨點法分析SKOV3-Neo和SKOV3-ΔG/A卵巢癌細胞經過17-AAG處理後HER2蛋白表現情形 40
第三節、合併ΔG/A和17-AAG對相較於單獨處理17-AAG可以顯著的抑制卵巢癌細胞轉型作用 41
壹、利用軟瓊脂膠分析細胞經17-AAG處理後對卵巢癌細胞轉型作用的影響 41
第四章、討論 43
第五章 結論 48
第六章 未來方向 49
第七章 參考文獻 50
第一節、圖 60
附錄 69
附錄一、HSP90在蛋白質摺疊循環中所扮演的角色 69
附錄二、HSP90在癌症六大特性的訊息分子調控中扮演重要的角色 70
附錄三、細胞存活率檢測試劑物質結構及其最大吸收光值 71
附錄四、配製17-AAG儲備溶液流程圖及藥物處理作用濃度 72
附錄五、利用BSA建立蛋白質標準曲線 74
附錄六、SDS-PAGE膠體配製方法及膠體百分比 75
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