臺灣博碩士論文加值系統

　　肺癌是目前全球癌症死亡率最高的疾病之一，肺癌病患死亡主要原因是癌細胞發生轉移。癌細胞轉移的過程中會有許多複雜的機制參與其中，當然也牽涉到許多不同功能的基因。本研究的主要目的是要篩選並建立出與肺癌轉移相關的基因，並進ㄧ步探討癌細胞轉移的分子作用機制。在本研究中使用微陣列技術以及肺癌轉移模式細胞株，篩選出與癌轉移相關的基因。本研究針對所篩選出可能的癌轉移相關基因Desmocollin-2進行深入的探討。在本研究結果顯示在高度轉移能力的肺癌細胞株中如A549與CL1-5其Desmocollin-2基因的表現量相對較少於低轉移能力的CL1-0肺癌細胞株，這個結果說明Desmocollin-2基因的表現與肺癌細胞的轉移及侵入能力呈現負相關。利用shRNA-DSC的表現載體抑制Desmocollin-2基因表現後，我們發現抑制Desmocollin-2基因的表現會促進肺癌細胞的生長以及移動能力，同時也促進了肺癌細胞的群落形成能力。最後發現在穩定抑制Desmocollin-2基因的細胞株其生長形態出現Epithelial to mesenchymal transition (EMT)的現象，這些實驗的結果都證明了Desmocollin-2基因在肺癌細胞中扮演抑制轉移的角色。

Lung cancer is the most common cause of cancer death in the world, and lung cancer patients death mainly due to metastasis. The process of metastasis have many complex mechanisms involved, consist of many different functional genes. The main purpose of this study is screening with lung cancer metastasis-related genes, and thus further explore the molecular mechanisms of cancer metastasis. Previously, using microarray assay and lung cancer metastasis model cell lines, screening with cancer metastasis-related genes. Additionally, we focus on cancer metastasis-related gene, Desmocollin-2. In this study, Desmocollin-2 expression in highly metastatic lung cancer cell lines (such as A549 and CL1-5) is fewer than low metastatic lung cancer cell (CL1-0), these result have proved that Desmocollin-2 gene expression levels in lung cancer cells were negatively correlation with the metastasis activity of a panel of lung cancer cell lines. Using shRNA-DSC2 transfection methods, we suggested that knockdown DSC2 gene expression can promote lung cancer cells proliferation and migration, at the same time inhibit Desmocollin-2 gene expression also promote lung cancer cells colonyforming. Finally found that stable suppression Desmocollin-2 gene in cells whose morphology similar Epithelial to mesenchymal transition (EMT) phenomenon, These result have proved that Desmocollin-2 may play a role in tumor suppressor.

封面內頁.
簽名頁.
中文摘要. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii
英文摘要. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iv
誌謝. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v
目錄. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .ix
圖目錄. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .xii

1.　前言…………………………………………………………………………………………………………………………………………………1
1.1 癌症…………………………………………………………………………………………………………………………………………………1
1.2 肺癌…………………………………………………………………………………………………………………………………………………2
1.3 致癌基因與腫瘤抑制基因…………………………………………………………………………………………………………4
1.4 癌轉移與相關基因的研究…………………………………………………………………………………………………………6
1.5 Desmosome…………………………………………………………………………………………………………………………………9
1.6 Desmocollin-2 (DSC2) 基因和已知的功能……………………………………………………………11
1.7 Desmocollin-2 (DSC2) 基因和癌症之間的研究……………………………………………………12
1.8 β-catenin………………………………………………………………………………………………………………………………14
1.9 EGFR………………………………………………………………………………………………………………………………………… 15
2. 研就動機…………………………………………………………………………………………………………………………………………18
3. 實驗設計與流程……………………………………………………………………………………………………………………………19
4. 材料方法…………………………………………………………………………………………………………………………………………20
4.1 細胞株……………………………………………………………………………………………………………………………………………20
4.2 細胞繼代………………………………………………………………………………………………………………………………………20
4.3 細胞凍存………………………………………………………………………………………………………………………………………21
4.4 轉染…………………………………………………………………………………………………………………………………………………21
4.5 RNA萃取…………………………………………………………………………………………………………………………………………22
4.6 RNA去除DNA處理…………………………………………………………………………………………………………………………22
4.7 cDNA合成反應………………………………………………………………………………………………………………………………23
4.8 即時定量PCR…………………………………………………………………………………………………………………………………23
4.9 建立抑制DSC2表現之系統…………………………………………………………………………………………………………24
4.10 菌種保存………………………………………………………………………………………………………………………………………25
4.11 質體DNA萃取………………………………………………………………………………………………………………………………25
4.11.1傳統法質體DNA萃取………………………………………………………………………………………………………………25
4.11.2 質體DNA之kit萃取……………………………………………………………………………………………………………26
4.12 DNA電泳………………………………………………………………………………………………………………………………………27
4.13 DNA膠體kit純化………………………………………………………………………………………………………………………28
4.14 MTT assay………………………………………………………………………………………………………………………………28
4.15 Colony formation assay……………………………………………………………………………………………29
4.16 細胞遷移分析 ( Cell migration assay )……………………………………………………………29
4.16.1 wound healing assay…………………………………………………………………………………………………29
4.16.2 Transwell migration assay ………………………………………………………………………………30
4.17 西方墨點分析 ( Western Blot ) ………………………………………………………………………………31
4.16.1 SDS膠體的製備………………………………………………………………………………………………………………………31
4.16.2 蛋白質樣品製備………………………………………………………………………………………………………………………32
4.16.3 蛋白質的定量……………………………………………………………………………………………………………………………32
4.16.4 SDS膠體電泳……………………………………………………………………………………………………………………………33
4.16.5 電轉……………………………………………………………………………………………………………………………………………33
4.16.6 抗體雜合……………………………………………………………………………………………………………………………………34
4. 結果………………………………………………………………………………………………………………………………………………………36
4.1 透過microarry assay的分析比較CL1-5以及CL1-0細胞中的基因表現情形………………………………………………………………………………………………36
4.2 藉由即時定量PCR的方式分析CL1-5以及CL1-0肺癌細胞中的基因表現情形……………………………………………………………………………………………………36
4.3 以及時定量PCR的方式分析Desmocollin-2-ab在侵入能力不同的細胞株中mRNA表現量的差異………………………………………………………………36
4.4 針對Desmocollin-2的兩種異構物以及時定量PCR的方式分析不同的細胞株中表現量的差異……………………………………………………………………37
4.5 以西方墨點法分析Desmocollin-2在侵入能力不同的肺癌細胞株中蛋白質表現量的差異……………………………………………………………………………37
4.6 以即時定量PCR的方式分析shDSC2的抑制效果……………………………………………………………………………………………………………………………………………………………38
4.7 以wound healing assay 來分析其Transient transfection shDSC2-497、pGIPZ的CL1-0細胞的移動能力…………………39
4.8 以colonyformation assay 分析Transient transfection shDSC2、pGIPZ的CL1-0細胞群落形成的能力………………………39
4.9 以MTT assay分析Transient transfection shDSC2、pGIPZ的CL1-0細胞的增生速度…………………………………………………………………40
4.10 以即時定量PCR的方式檢測轉染shDSC2的CL1-0細胞株…………………………………………………………………………………………………………………………………………40
4.11 以西方墨點法分析穩定抑制Desmocollin-2基因mRNA的細胞株…………………………………………………………………………………………………………………………41
4.12 以transwell migration分析穩定抑制Desmocollin-2基因的CL1-0細胞株…………………………………………………………………………………………41
4.13 以colonyformation assay分析穩定抑制Desmocollin-2基因的CL1-0細胞株其細胞群落形成的能力…………………………………………42
4.14 以MTT assay分析穩定抑制Desmocollin-2基因的CL1-0細胞株增生的速度………………………………………………………………………………………………42
4.15 分析穩定抑制Desmocollin-2基因的CL1-0細胞株增生情形………………………………………………………………………………………………………………………………43
4.16 觀察穩定抑制Desmocollin-2基因的CL1-0細胞型態……………………………………………………………………………………………………………………………………………43
5. 結論…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………45
參考文獻…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………66
附錄…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………85

圖目錄

圖1. 透過microarry assay的分析比較CL1-5以及CL1-0肺癌細胞中的基因表現情形…………………………………………………………………………………………50
圖2. 藉由即時定量PCR的方式去分析CL1-5以及CL1-0肺癌細胞中的基因表現情形……………………………………………………………………………………………………51
圖3. 以及時定量PCR的方式分析Desmocollin-2-ab在侵入能力不同的細胞株中mRNA表現量的差異…………………………………………………………………52
圖4. 針對Desmocollin-2的兩種異構物以及時定量PCR的方式分析不同的細胞株中表現量的差異………………………………………………………………………53
圖5. 以西方墨點法分析Desmocollin-2在侵入能力不同的肺癌細胞株中蛋白質表現量的差異………………………………………………………………………………54
圖6. 以即時定量PCR的方式分析shDSC2的抑制效果………………………………………………………………………………………………………………………………………………………………55
圖7. 以wound healing assay 來分析其Transient transfection shDSC2-497、pGIPZ的CL1-0細胞的移動能力……………………56
圖8. 以colonyformation assay 分析Transient transfection shDSC2、pGIPZ的CL1-0細胞群落形成的能力…………………………57
圖9. 以MTT assay分析Transient transfection shDSC2、pGIPZ的CL1-0細胞的增生速度……………………………………………………………………58
圖10. 以即時定量PCR的方式檢測轉染shDSC2的CL1-0細胞株……………………………………………………………………………………………………………………………………………59
圖11. 以西方墨點法分析穩定抑制Desmocollin-2基因mRNA的細胞株……………………………………………………………………………………………………………………………60
圖12. 以transwell migration分析穩定抑制Desmocollin-2基因的CL1-0細胞株……………………………………………………………………………………………61
圖13. 以colonyformation assay分析穩定抑制Desmocollin-2基因的CL1-0細胞株其細胞群落形成的能力……………………………………………62
圖14. 以MTT assay分析穩定抑制Desmocollin-2基因的CL1-0細胞株增生的速度…………………………………………………………………………………………………63
圖15. 分析穩定抑制Desmocollin-2基因的CL1-0細胞株增生情形…………………………………………………………………………………………………………………………………64
圖16. 觀察穩定抑制Desmocollin-2基因的CL1-0細胞型態………………………………………………………………………………………………………………………………………………65

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