臺灣博碩士論文加值系統

當細胞生長因子受體 (growth factor receptor) 過度表現，常導致受體以不需配體 (ligand-independent) 的方式活化。在人類表皮癌細胞A431中，持續活化的肝細胞生長因子受體 (hepatocyte growth factor receptor, Met) 及上皮細胞生長因子受體 (epidermal growth factor receptor, EGFR) 賦予細胞增生及侵犯的潛能。本研究發現在A431細胞中，不需配體方式活化的Met及EGFR依賴細胞附著到基質 (substratum) 上，且與細胞攤附 (cell spreading)、胞外基質蛋白的種類、基質的軟硬等無關；這種細胞附著引起的Met及EGFR活化亦非肇因於Src的活化，以及活性氧自由基 (reactive oxygen species, ROS) 的產生或者是細胞骨架的完整性。此外，細胞附著引起Met與EGFR的活化途徑係彼此相互獨立。但Met及EGFR表現量的降低，會影響細胞附著所引起的活化，因此受體的過度表現在此種細胞附著引起的自我活化是不可或缺的。本研究同時亦進一步發現當細胞重新貼附 (replating) 時，lipid rafts會聚集在細胞貼附基底的部分；且利用methyl-beta-cyclodextrin吸附細胞膜上膽固醇而擾亂lipid rafts的分布後，發現當細胞貼附時Met的活性受到抑制時，EGFR的活性反而上升。雖然活化的Met及EGFR均分布於0.04% Triton的可溶部分 (換言之，非rafts的部分)，但是利用methyl-beta-cyclodextrin擾亂lipid rafts的分布，確實對Met及EGFR有著不同的影響。因此，本研究證明在A431細胞lipid rafts可能參與細胞附著所引起的Met及EGFR之活化。

Overexpression of growth factor receptors often leads to their activation in a ligand-independent manner. In this study, I demonstrate that the hepatocyte growth factor receptor Met and epidermal growth factor receptor (EGFR) are constitutively activated in human epidermal carcinoma A431 cells, which confers proliferative and invasive potentials to the cells. The ligand-independent activation of Met and EGFR in A431 cells relies on cell attachment to a substratum, but is independent of cell spreading, extracellular matrix proteins, and substratum stiffness. This cell attachment-induced activation of Met and EGFR cannot be attributed to Src activation, production of reactive oxygen species, and the integrity of the cytoskeleton. In addition, I demonstrate that Met and EGFR are independently activated upon cell attachment. However, partial depletion of Met and EGFR prevents their activation upon cell adhesion, suggesting that overexpression of the receptors is a prerequisite for their self-activation upon cell attachment. Moreover, I discover that the distribution of lipid rafts is limited at the area of basal surface when cells are replated. Disruption of lipid rafts by depletion of membrane cholesterol with methyl-beta-cyclodextrin impairs Met activation, but enhances EGFR activation upon cell attachment. Although the majority of both active Met and EGFR are detected in the 0.04% Triton-soluble fractions (i.e. non-raft fraction), disturbance of lipid rafts by methyl-beta-cyclodextrin has opposite impacts to Met and EGFR. Therefore, it is possible that lipid rafts are involved in regulation of attachment-induced activation of Met and EGFR in A431 cells.

摘要 1
Abstract 2
目錄 3
Ⅰ. 前言 6
Ⅱ. 文獻探討 7
一、肝細胞生長因子受體 7
二、上皮細胞生長因子受體 9
三、RTKs與腫瘤 10
四、Lipid rafts 11
五、細胞貼附與lipid rafts 13
六、Lipid rafts與腫瘤 14
七、細胞貼附與RTKs 14
八、機械性感受器 16
Ⅲ. 材料與方法 18
一、實驗材料 18
1. 細胞株 18
2. Short hairpin RNAs (shRNAs) and the target sequences 18
3. 抗體 18
4. 藥品 19
5. 儀器 21
二、實驗方法 21
1. 細胞培養 21
2. 細胞蛋白質之萃取 21
3. 西方墨點法 22
4. 慢病毒的製造與感染 22
5. 細胞侵犯實驗 23
6. 細胞聚集實驗 23
7. 製備polyacrylamide膠 23
8. 免疫螢光染色及共軛焦顯微鏡掃描 24
9. 倒立式雷射全內反射顯微鏡 25
10.分離lipid rafts 25
Ⅳ. 結果 26
一、以不需配體方式活化的Met與EGFR提供A431細胞生長及侵犯的優勢 26
二、以不需配體方式活化的Met與EGFR需依賴細胞貼附至細胞外基質 27
三、細胞貼附引起的Met與EGFR活化，與Src、活性氧自由基、或細胞骨架的完整性等無關 28
四、細胞貼附引起的Met與EGFR活化是彼此獨立並不互相影響 29
五、Met與EGFR的過度表現與自我聚集對細胞貼附引起的活化是必要的 30
六、Lipid rafts可能參與細胞貼附所引起的Met與EGFR活化 30
Ⅴ. 討論 32
Ⅵ. 引用文獻 38
Ⅶ. 附圖 49
圖1. A431細胞株中的Met與EGFR都持續活化 49
圖2. 抑制Met與EGFR的表現，分別選擇性抑制下游ERK或STAT3磷酸化 50
圖3. 以不需配體方式活化的Met與EGFR提供A431細胞生長上的優勢 51
圖4. 以不需配體方式活化的Met與EGFR提供A431細胞侵犯能力的優勢 52
圖5. 細胞與細胞間的貼附不能引起Met與EGFR的活化 53
圖6. 細胞貼附引起Met與EGFR以不需配體的方式活化 54
圖7. 細胞貼附引起Met與EGFR的活化與細胞外基質種類無關 55
圖8. 抑制Integrin β1的表現不影響細胞貼附引起的Met與EGFR活化 56
圖9. 基質的軟硬度不影響細胞貼附引起的Met與EGFR活化 57
圖10. 細胞貼附引起的Met與EGFR活化不倚賴Src 58
圖11. 細胞貼附引起的Met與EGFR活化不倚賴reactive oxygen species (ROS) 59
圖12. 細胞貼附引起的Met與EGFR活化不倚賴肌動蛋白絲 60
圖13. 細胞貼附引起的Met與EGFR活化不倚賴微小管 61
圖14. 抑制Met活性不影響EGFR的活性 62
圖15. 抑制Met表現不影響EGFR的活性 63
圖16. 抑制EGFR表現不影響Met的活性 64
圖17. Met的過度表現對其自我活化是必要的 65
圖18. EGFR的過度表現對其自我活化是必要的 66
圖19. 降低Met表現量不影響它們接受HGF的刺激活化 67
圖20. 降低EGFR表現量不影響它們接受EGF的刺激活化 68
圖21. Lipid rafts與Met在細胞貼附時的分布 69
圖22. Lipid rafts與EGFR在細胞貼附時的分布 70
圖23. Lipid rafts被侷限分布在細胞貼附的底部 71
圖24. MβCD擾亂lipid rafts的分布 72
圖25. 活化的Met與EGFR都位在非lipid rafts的部分 73
圖26. MβCD作用下對Met及EGFR的活性有相反的影響 74
圖27. 細胞重新貼附時MβCD的作用對Met及EGFR的活性有相反的影響 75

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