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論文名稱 Title |
蛋白質體學之大腸直腸癌差異性蛋白質表現分析 Proteomic analysis of differentially expressed proteins in colorectal cancer |
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系所名稱 Department |
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畢業學年期 Year, semester |
語文別 Language |
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學位類別 Degree |
頁數 Number of pages |
171 |
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研究生 Author |
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指導教授 Advisor |
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召集委員 Convenor |
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口試委員 Advisory Committee |
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口試日期 Date of Exam |
2005-07-15 |
繳交日期 Date of Submission |
2005-08-16 |
關鍵字 Keywords |
二維電泳法、質譜儀、大腸直腸癌、蛋白質體學 SW620, CD2AP, 2D, SW480, Oxaliplatin, MALDI-TOF, HT-29, Proteomics, 5-Fu, PTTG1 |
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統計 Statistics |
本論文已被瀏覽 5694 次,被下載 5336 次 The thesis/dissertation has been browsed 5694 times, has been downloaded 5336 times. |
中文摘要 |
本實驗經由收集外科手術所取得的大腸直腸癌癌化組織與正常組織,來進行蛋白質差異性表現研究,收集的癌症檢體其癌化程度分別有T1~T4時期等樣品(依TNM系統分類),我們利用二維電泳法與質譜鑑定技術來分析並經由統計分析定義出十八種差異性表現的蛋白質。本實驗結果顯示有十三種在腫瘤組織中會表現量上升的差異性蛋白質,分別是Keratin 8、Protein disuflde isomerase A3 precursor、 Keratin 18、Fractalkine precursor、LDH-B、 Tropomyosin alpha 4 chain、Tropomyosin alpha 3 chain、chloride intracellular channel protein 1、PTTG1(Pituitary tumor-transforming protein 1)、 |
Abstract |
We gathered normal and colorectal cancer tissues from 18 patients after tumor surgery. The tumor tissues represent caner stages from T1 to T4 (TNM system).Two-dimensional electrophoresis and MALDI-TOF techniques were utilized to identify the differentially expressed proteins. Our studies showed that there are about 18 differentially expressed proteins in normal and tumor tissues (p<0.05) which 13 proteins increased in tumor were Keratin 8, Protein disuflde isomerase A3 precursor, Keratin 18, Fractalkine precursor, LDH-B, Tropomyosin alpha 4 chain, Tropomyosin alpha 3 chain, chloride intracellular channel protein 1, PTTG1(Pituitary tumor-transforming protein 1), |
目次 Table of Contents |
Contents 中文摘要……………………………………………………………1 英文摘要…………………………………………………………… 2 英文縮寫表………………………………………………………… 3 壹、前言…………………………………………………………………5 一.大腸直腸癌之蛋白質分析與重要性………………………………5 1.1大腸直腸位置與解剖圖……………………………………………6 1.2大腸直腸癌好發區域………………………………………… 6 1.3病理特性與分期……………………………………………………7 1.4大腸直腸癌之病因學………………………………………………9 1.4.1偶發性大腸直腸癌………………………………………………10 1.4.2家族性多發腺瘤性息肉(Familial Adenomatous Polyposis,FAP)…12 1.4.3遺傳性非息肉性大腸直腸癌 (Hereditary Nonpolyposis Colorectal Cancer,HNPCC)…………………14 1.5篩檢與治療…………………………………………………………15 1.5.1化學治療…………………………………………………………16 二.蛋白質體學(Proteomics)及其定義………………………………17 三.基質輔助雷射脫附游離質譜分析法(MALDI-TOF/MS)……………18 (1)直線型TOF…………………………………………………………19 (2)反射型TOF…………………………………………………………19 四.蛋白質體學在大腸直腸癌上的應用(Proteomics of study colorectal cancer)…21 五.研究目標…………………………………………………………22 貳、實驗流程(Experiment flowchart)……………………………23 參、材料與方法(Materials and Methods)…………………… 27 一.大腸直腸組織樣品處理……………………………………………27 1.檢體來源………………………………………………………… 27 2.大腸直腸癌病人血液與組織蛋白質萃取…………………………27 2.1血液蛋白質萃取…………………………………………………27 2.2組織蛋白質萃取……………………………………………………27 2.3大腸直腸癌細胞株SW480、SW620、HT-29之蛋白質萃取………28 2.4 TCA/Actone沉澱…………………………………………………28 2.5蛋白質定量…………………………………………………………28 3.二維電泳法……………………………………………………… 29 3.1 Isoeletric focusing electrophoresis(聚電焦電泳)………29 3.2 Immobiline Drystrip Equilibration…………………………29 3.3 Sodiumdodecylsufate Polyacrylamide Gel Electrophoresis(SDS-PAGE)(聚丙烯酼胺膠體電泳)…………………………………30 3.4 Silver stain 銀離子染色………………………………………31 3.5 Coomassie brilliant blue R-250 stain……………………31 4.Gel imaging analysis 膠體影像分析及統計分析……………32 5.In gel digestion…………………………………………………32 5.1清洗(Washing)……………………………………………………32 5.2 Coomassie brilliant blue R-250 stain退染………………32 5.3 Reduction/Alkylation…………………………………………33 5.4 Digestion/Extraction…………………………………………33 5.5 MALDI-TOF質譜操作………………………………………………33 5.6 PSD(Post Source Decay)(Tandem TOF/TOF MS)操作…………34 5.7使用ProteinProspector之MS-Fit來辨認未知的蛋白質………34 6.西方墨點電泳法(Western blotting)……………………………34 6.1 COX2蛋白質表現測試……………………………………………35 6.2 CD2AP蛋白質表現測試……………………………………………36 6.3 PTTG1蛋白質表現測試…………………………………………36 二.大腸直腸癌RNA萃取………………………………………………36 1.Total RNA抽取……………………………………………………36 2.將mRNA反轉錄成cDNA……………………………………………37 3. PCR聚合酶連鎖反應………………………………………………37 4. PCR引子之設計……………………………………………………38 三.大腸直腸癌細胞株SW480、SW620、HT-29之培養與處理………39 1.材料…………………………………………………………………39 2.冷凍細胞解凍程序…………………………………………………39 3.細胞繼代培養(subculture)與細胞計數…………………………40 4.細胞冷凍程序………………………………………………………40 5.MTT抗癌活性測試…………………………………………………41 5.1細胞計數與種植(Seeding)………………………………………41 5.2加藥(Treatment 5-Fu or Oxaliplatin anti-cancer drugs)41 5.3加入MTT…………………………………………………………41 5.4加入DMSO……………………………………………………………41 5.5 ELISA reader……………………………………………………42 肆、實驗結果(Results)……………………………………………43 一.大腸直腸癌檢體之分析結果……………………………………43 二.二維電泳膠片之分析結果………………………………………43 2.1大腸直腸癌正常組織與癌化組織之二維電泳膠片分析………43 2.2軟體比對分析與統計差異性與非差異性之二維電泳膠片上之spot...................................................44 三.MALDI-TOF質譜分析與蛋白質資料庫比對……………………45 3.1 MS質譜分析……………………………………………………45 3.2差異性蛋白質身份鑑定………………………………………45 四.差異性蛋白質伴隨癌化過程中之各個時期表現…………………46 4.1伴隨在癌化過程表現上升的差異性蛋白質………………………46 4.2隨著癌化過程表現下降的差異性蛋白質…………………………48 五.Tandem(TOF/TOF) Mass spectrometry質譜分析結果…………49 六.大腸直腸癌組織RT-PCR結果分析…………………………………50 (A) Keratin在組織中RT-PCR之表現…………………………… 50 (B) PTTG1在組織中RT-PCR之表現……………………………… 50 (C) RAB11A在組織中RT-PCR之表現………………………………50 (D) CD2AP在組織中RT-PCR之表現…………………………………50 (E) VAMP-B/C在組織中RT-PCR之表現………………………………51 七.大腸直腸癌組織之西方點墨法結果分析(Western blotting)…51 7.1 COX2(Ptgs2)蛋白質表現之結果…………………………………51 7.2 CD2AP蛋白質表現之結果…………………………………………51 八.大腸直腸癌癌細胞株抗癌活性測試………………………………51 8.1利用抗癌藥5-Fu treatment SW480、SW620、HT-29等大腸直腸癌細胞株後期存活率之結果……………………………………………51 8.2利用抗癌藥Oxaliplatin treatment SW480、SW620、HT-29等大腸直腸癌細胞株後期存活率之結果…………………………………53 九.大腸直腸癌細胞株之二維電泳圖結果分析………………………54 十.大腸直腸癌細胞株之CD2AP、PTTG1之western blotting結果分析.......................................................54 伍、實驗討論(Discussion).................................56 一.大腸直腸癌組織之二維電泳實驗討論……………………………56 二.差異性蛋白質之RT-PCR實驗討論…………………………………57 2.1 PTTG1………………………………………………………………58 2.2 RAB11A……………………………………………………………58 2.3 CD2AP………………………………………………………………58 2.4 VAMP-B/C…………………………………………………………58 三.大腸直腸癌組織差異性蛋白質之western blot實驗討論………58 四.大腸直腸癌細胞株SW480、SW620、HT-29利用藥物處理後之存活率實驗討論...............................................59 五.大腸直腸癌細胞株差異性蛋白質CD2AP與PTTG1之western blot實驗討論...................................................59 六.差異性蛋白質之介紹與討論………………………………………61 6.1 PTTG1……………………………………………………………62 6.2 CD2AP……………………………………………………………64 6.3 Tropomyosin……………………………………………………66 6.4 Alpha-1-antitrypsin…………………………………………67 6.5 RAB11A…………………………………………………………68 6.6 VAMP-B/C………………………………………………………68 6.7 StARD5…………………………………………………………69 6.8 Fractalkine (CX3CL1)………………………………………70 6.9 CLIC1(NCC27)…………………………………………………71 6.10 Peroxiredoxin 2……………………………………………71 陸、結論與展望………………………………………………………73 柒、參考文獻(Reference)……………………………………………74 捌.圖與表(Figures & Tables Contents)…………………………77 文獻探討(Literature Review) 圖一.大腸直腸位置與解剖圖…………………………………………6 圖二.大腸腸道剖面圖…………………………………………………7 圖三. Molecular events that characterize the transition to adenocarcinoma..........................................12 圖四. The Wnt signaling pathway…………………………………14 圖五.直線型TOF與反射型TOF…………………………………………20 表一. AJCC/UICC TNM. Definition*…………………………………8 表二. AJCC/UICC Stage Groupings…………………………………8 材料與方法(Materials and Methods) 表三.經由NCBI Homepage所設計出來之RT-PCR引子………………37 實驗結果(Results) 表五.大腸直腸癌病患基本資料與臨床病徵一覽表…………………82 表六.大腸直腸癌蛋白質差異性表現一覽表…………………………83 表七.大腸直腸癌蛋白質未差異性表現一覽表………………………84 表八.大腸直腸癌隨癌化後表現增加之差異性蛋白質身分鑑定一覽表.......................................................85 表九.大腸直腸癌隨癌化後表現減少之差異性蛋白質身分鑑定一覽表.......................................................86 表十.大腸直腸癌隨癌化後無差異性表現之蛋白質身分鑑定一覽表.......................................................87 圖十. Master gel (Analytical gel)………………………………91 圖十一.~圖十五.大腸直腸癌差異性蛋白質表現之二維電泳圖……92 圖十六.大腸直腸癌癌化後差異性蛋白質表現增加之相對百分比關係圖………………………………………………………………………97 圖十七.大腸直腸癌癌化後差異性蛋白質表現減少之相對百分比關係圖………………………………………………………………………98 圖十八.~圖三十五.差異性蛋白質在大腸直腸癌組織中隨著癌化之不同時期表現趨勢圖……………………………………………………99 圖三十六.~圖三十八.MS/MS(PSD)質譜分析圖……………………108 圖三十九.~圖四十.RT-PCR之結果分析……………………………111 圖四十一. Western blotting analysis of COX2………………113 圖四十二. Western blotting analysis of CD2AP……………114 圖四十三.~圖四十四.大腸直腸癌細胞株加入5-Fu抗癌藥後細胞相對存活率趨勢圖…………………………………………………………115 圖四十五.~四十六.大腸直腸癌細胞株加入Oxaliplatin抗癌藥後細胞相對存活率趨勢圖…………………………………………………117 圖四十七.~五十二.2-D electrophoresis profile of human colorectal cancer cell lines of SW480、SW620 and HT-29…119 圖五十三.大腸直腸癌細胞株之差異性蛋白質CD2AP與PTTG1之Western bolting analysis…………………………………………125 實驗討論(Discussion) 圖六. Model of regulation of mitosis and G1 by APC-dependent cyclin proteolysis……………………………………63 圖七.Regulation of sister chromatid separation by the APC.....................................................63 圖八.CD2AP complex binding EGF…………………………………65 圖九.CD2AP complex binding VEGFR………………………………65 附錄(Appendix)………………………………………………126 圖五十四.~七十一.2-D electrophoresis profile of human colorectal cancer patient………………………………………127 圖七十二. 2-D electrophoresis profile of human colorectal cancer cell line of SW 480 and SW620………………………145 附圖一.~附圖十八.差異性蛋白質經過Trypsin分解片段的質譜分....................................................146 附表一.~附表十八.差異性蛋白質之MS peaks match coverage percentage............................................146 |
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