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研究生:劉錦誠
研究生(外文):Chin-Cheng Liu
論文名稱:製造對具有KRAS活化性突變的大腸直腸癌細胞有腫瘤分解能力之腺病毒
論文名稱(外文):Construction of an oncolytic adenovirus for KRAS activating mutant colorectal cancer cells
指導教授:蔡英傑蔡英傑引用關係劉俊煌劉俊煌引用關係
指導教授(外文):Ying-Chieh TsaiJin-Hwang Liu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:101
中文關鍵詞:腫瘤分解腺病毒KRAS活化性突變
外文關鍵詞:oncolytic adenovirusKRAS activating mutant
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中文摘要
剔除E1B-55kD基因區段(ΔE1B-55kD)的重組腺病毒,能分解具有p53突變或不表現p53的腫瘤細胞。然而許多腫瘤細胞具KRAS活化突變(KRASaMut),且表現自然型p53 (p53wild)。為增加ΔE1B-55kD重組腺病毒對腫瘤分解的應用性,使能分解表現自然型p53的腫瘤細胞,我們利用KRAS活化突變去引導human double minute 2 (hdm2)的表現進而中和自然型p53,而創作一個不拘腫瘤細胞p53突變或不突變的腫瘤分解重組腺病毒。hdm2的啟動子含KRAS和p53的調控區段,去除p53調控區段後,我們創作一個僅受KRASaMut調控的hdm2啟動子-Δp53REP2啟動子,並藉由啟動子報告系統實驗確定了其受KRASaMut調控的特異性。將藉由Δp53REP2去調控hdm2表現的系統導入ΔE1B-55kD的腺病毒內而製造出一種新的受KRASaMut調控的腫瘤分解重組腺病毒-Ad-KRhdm2。由細胞培養的群落性分解實驗(plaque forming assay)證實,Ad-KRhdm2除了與ΔE1B-55kD重組腺病毒一樣能分解具有p53突變的大腸直腸癌細胞(SW620 and HT29)外,Ad-KRhdm2對有KRASaMut大腸直腸癌細胞有選擇性的分解能力而不拘其p53基因的型態(HCT116, LoVo, LS174T and LS123)。根據細胞的病毒感染殘存試驗(cell viability assay)顯示,HCT116, LoVo, LS174T, LS123, and SW620等腫瘤細胞經Ad-KRhdm2重組腺病毒感染七日後,其降低50%細胞存活率時所需病毒感染劑量(CE50),低於對MRC5正常細胞及無KRASaMut或p53突變的RKO腫瘤細胞440至3400倍。Ad-KRhdm2 重組腺病毒對LoVo, LS174T及SW620腫瘤細胞的分解作用更証明於動物外殖腫瘤(xenograft assay)的實驗。存在KRAS活化突變與自然型p53 (KRASaMut /p53wild)的腫瘤細胞(HCT116, LoVo, and LS174T)經Ad-KRhdm2感染後,Hdm2的表現量會增加,而p53的表現量會降低,並具有抑制p53活化p21Cip1啟動子的能力。經實驗證實,Ad-KRhdm2重組腺病毒能分解有KRASaMut的腫瘤細胞而不拘p53基因的型態,相反地,對正常細胞無毒性,展示了Ad-KRhdm2進行臨床試驗的可行性與臨床治療潛力。

Abstract
E1B-55kD-deleted adenoviruses (ΔE1B-55kD Ads) have been used as conditionally replicative adenoviruses (CRAds) for therapeutic purpose in tumors with loss-of-function p53 mutation. To target cancer cells harboring activating mutant KRAS (KRASaMut) but spare p53wild normal cells, we constructed and examined by reporter assays a KRASaMut but not p53-responsive promoter, the ?愎53REP2 promoter. The ?愎53REP2 promoter, derived from human double minute 2 (hdm2) P2 promoter with its p53 response elements being deleted, was used to regulate the expression of hdm2 transgene in a novel ΔE1B-55kD CRAd, the Ad-KRhdm2. The Ad-KRhdm2 selectively replicated in and exerted cytopathic effects on KRASaMut colorectal cancer cell lines (HCT116, LoVo, LS174T, LS123, and SW620), regardless of their p53 gene statuses, by forming plaques and exhibiting cytopathic effect in cultured cells. Ad-KRhdm2, like other ΔE1B-55kD Ads, also exerted selective cytopathic effects on tumor cells with loss-of-function p53 mutant. The multiplicities of infection (MOIs) of Ad-KRhdm2 required to decrease 50% viability of KRASaMut tumor cells cultured for 7 days were 440 to 3400-time less than those of MRC5 normal fibroblasts and KRASwild/p53wild RKO tumor cells. Intratumoral injection of Ad-KRhdm2 vectors exhibited specific lytic activities in nude mouse xenografts of KRASaMut cell lines (LoVo, SW620, and LS174T) but not in xenografts of RKO cells. Transduction of KRASaMut /p53wild HCT116, LoVo, and LS174T cells by Ad-KRhdm2 significantly increased Hdm2 expression, decreased p53 level, and abolished the p53-transactivating p21Cip1 promoter activity. The Ad-KRhdm2 has demonstrated its therapeutic potential in KRASaMut cancer cells and warrants further clinical trials.

Index
Index ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧01
中文摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧04
Abstract‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧06
一、 緒論
1. 研究背景‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧08
2. 腺病毒簡介
2.1腺病毒的基本構造‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧09
2.2腺病毒的複製‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧11
2.3腺病毒早期蛋白的功能‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧12
2.4腺病毒的特性‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧14
3. 腫瘤分解腺病毒
3.1腫瘤分解腺病毒的背景‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧15
3.2腫瘤分解腺病毒的應用性‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧16
4. KRAS簡介
4.1 KRAS的性質‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧17
4.2 RAS的轉譯後修飾作用‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧18
4.3 RAS的訊息傳遞‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧19
4.4 KRAS活化突變與癌症‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧21
4.5以RAS訊息傳遞為標的所設計的藥物‧‧‧‧‧‧‧‧‧‧‧‧‧‧21
5. p53簡介
5.1 p53的性質‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧22
5.2 DNA損傷會造成p53的活化‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧25
5.3 p53的調控‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧26
6. Hdm2簡介
6.1 Hdm2的性質‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧27
6.2 Hdm2與p53的相互作用‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧27
6.3 p14ARF調節Hdm2蛋白的功能‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧28
6.4 Hdm2的表現受到KRAS的調控‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧29
6.5 Hdm2的上游調節者‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧30
6.6 Hdm2的下游作用者‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧31


二、實驗材料與方法
1. 實驗用細胞株及細胞培養方法
1.1 實驗用細胞株的特性‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧33
1.2 實驗細胞株培養條件‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧35
2. 製作剔除p53反應區段的hdm2 P2啟動子
2.1 製作pΔp53REP2-Luc報告載體‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧36
2.2 測試KRAS調控pΔp53REP2-Luc報告載體的能力‧‧‧‧‧‧‧‧‧‧38
3. 製作重組腺病毒
3.1 製作轉殖基因序列‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧40
3.2 pAdEasy-1與pShuttle進行重組‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧41
3.3 製作完整重組腺病毒顆粒‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧42
3.4 純化重組腺病毒顆粒‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧43
3.5 鑑定重組腺病毒所含轉殖基因之正確性‧‧‧‧‧‧‧‧‧‧‧‧‧44
3.6 測定重組腺病毒效價‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧45
4. 評估重組腺病毒的感染力
4.1 分析實驗細胞株內CAR表現情形‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧45
4.2 評估重組腺病毒在感染細胞內複製能力‧‧‧‧‧‧‧‧‧‧‧‧‧46
4.3 評估感染細胞能否釋放重組腺病毒顆粒‧‧‧‧‧‧‧‧‧‧‧‧‧47
5. 分析細胞內Hdm2、p53及p14ARF蛋白的表現情形‧‧‧‧‧‧‧‧‧‧‧47
6. 評估重組腺病毒對p53功能的影響‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧49
7. 分析重組腺病毒對實驗細胞株的毒殺能力
7.1細胞存活率試驗‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧50
7.2細胞培養的群落性分解實驗‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧51
7.3利用裸鼠外殖腫瘤模式試驗重組腺病毒的腫瘤毒殺能力‧‧‧‧‧‧‧52
三、實驗結果
1. hdm2 Δp53REP2啟動子受KRASaMut調控,而不受p53影響‧‧‧‧‧‧‧54
2. 純化後的重組腺病毒皆含有正確的轉殖基因‧‧‧‧‧‧‧‧‧‧‧‧‧55
3. 所製作重組腺病毒對實驗細胞株具有感染力‧‧‧‧‧‧‧‧‧‧‧‧‧55
4. Ad-KRhdm2轉染KRASaMut腫瘤細胞後,Hdm2的表現與p53相反‧‧‧56
5. p53轉活化p21Cip1啟動子的能力被Ad-KRhdm2抑制‧‧‧‧‧‧‧‧‧‧57
6. p14ARF的表現受重組腺病毒影響‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧58
7. Ad-KRhdm2對KRASaMut腫瘤細胞有選擇性的毒殺作用‧‧‧‧‧‧‧58
8. 在裸鼠外殖腫瘤模式中,Ad-KRhdm2對KRASaMut腫瘤細胞具有毒殺力‧60
四、結論‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧63
五、討論
1. Ad-KRhdm2對KRASaMut腫瘤細胞有選擇性毒殺能力‧‧‧‧‧‧‧‧65
2. 在人類與老鼠細胞中,mdm2 P2啟動子對RAS活化路徑的反應不同‧‧66
3. 大量表現Hdm2能抵銷p14ARF的抑制作用‧‧‧‧‧‧‧‧‧‧‧‧‧67
4. Ad-KRhdm2比Ad-E1與Ad-Δp53REP2有較高的腫瘤毒殺能力‧‧‧‧68
5. 過度表現p53蛋白的重組腺病毒也具有腫瘤毒殺效果‧‧‧‧‧‧‧‧69
6. 合併使用化學藥物與Ad-KRhdm2能增加治療癌症的效果‧‧‧‧‧‧‧70
六、未來實驗方向‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧71
七、參考文獻‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧72
八、表
表一、實驗使用細胞株的KRAS與p53基因型態‧‧‧‧‧‧‧‧‧‧‧‧84
表二、實驗所用引子序列‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧85
表三、實驗所用重組腺病毒的效價‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧86
表四、重組腺病毒感染細胞七天後,細胞50%死亡的病毒感染劑量(MOI) 87
九、圖
圖一、建構Δp53REP2啟動子示意圖‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧88
圖二、所建構Δp53REP2啟動子的DNA定序圖‧‧‧‧‧‧‧‧‧‧‧‧89
圖三、Δp53REP2啟動子在細胞株中活化的情形‧‧‧‧‧‧‧‧‧‧‧‧90
圖四、製作重組腺病毒所用之轉殖基因‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧91
圖五、製備重組腺病毒流程圖‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧92
圖六、個別重組腺病毒內所含轉殖基因之電泳圖‧‧‧‧‧‧‧‧‧‧‧‧93
圖七、實驗用細胞株內CAR表現情形‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧94
圖八、重組腺病毒感染細胞株後,腺病毒hexon蛋白的表現情形‧‧‧‧‧95
圖九、重組腺病毒感染細胞株後,測定培養液中E1A基因的電泳圖‧‧‧96
圖十、重組腺病毒對感染細胞株內Hdm2蛋白含量的影響‧‧‧‧‧‧‧‧97
圖十一重組腺病毒對感染細胞株內p53蛋白含量的影響‧‧‧‧‧‧‧‧‧98
圖十二、重組腺病毒對感染細胞株內p14ARF蛋白含量的影響‧‧‧‧‧‧99
圖十三、重組腺病毒對Δp53REP2啟動子在細胞株中轉活化的影響‧‧‧‧100
圖十四、重組腺病毒感染細胞株七日後,細胞的存活率‧‧‧‧‧‧‧‧‧101
圖十五、重組腺病毒對感染細胞株的溶解作用‧‧‧‧‧‧‧‧‧‧‧‧‧102
圖十六、重組腺病毒於裸鼠外殖腫瘤模式中對腫瘤細胞的毒殺能力‧‧‧‧104

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