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研究生:吳芝嫻
研究生(外文):Chih-Hsien
論文名稱:氯化鎳誘導人類支氣管上皮細胞進行上皮-間質轉換及其作用機制之研究
論文名稱(外文):The mechanisms of epithelial mesenchymal transition induced by nickel chloride in human bronchial epithelial cells
指導教授:柯俊良柯俊良引用關係
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學分子毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
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
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細胞進行上皮-間質型轉換過程 (epithelial-mesenchymal transition, EMT) 是肺纖維化和腫瘤轉移前的重要程序,在此過程中,細胞與細胞間結合的標記蛋白E-cadherin會減少,間質型標記蛋白fibronectin和vimentin的表現會增加,並且許多不同的訊息傳遞路徑參與其中。已知鎳化合物能夠造成肺部癌化以及對健康產生不良影響,然而目前仍不清楚鎳是否會誘導細胞進行上皮-間質轉換過程。我們的研究主要探討鎳是否誘發人類支氣管上皮細胞產生上皮-間質轉換現象以及相關基因表現,並且釐清氯化鎳啟動細胞進行上皮-間質轉換之可能分子機制。首先將BEAS-2B細胞暴露於鎳化合物,運用RT-PCR和免疫轉漬法觀察E-cadherin和fibronectin的表現量,觀察到氯化鎳誘導E-cadherin減少以及fibronectin增加,造成細胞產生上皮-間質轉換的現象。另外,在一維電泳分析偵測出,氯化鎳可減少Annexin 2的蛋白表現;NF-κB抑制劑BAY11-7082可降低氯化鎳所誘導的fibronectin表現量,但較不影響E-cadherin的變化。運用ROS抑制劑、DNA甲基轉移酶抑制劑、histone去乙醯基酶抑制劑以及蛋白酶體抑制劑等配合使用流式細胞儀、免疫轉漬法,研究氯化鎳調控E-cadherin的作用機制,觀察到ROS抑制劑NAC能部分減緩氯化鎳所誘導的EMT現象,並且抑制氯化鎳所誘導的HIF-1α和LCN2表現;DNA甲基轉移酶抑制劑5-Aza-dc也可減緩氯化鎳降低E-cadherin表現,並且藉由甲基特異性連鎖反應分析,發現氯化鎳可增進E-cadherin的promoter高度甲基化;histone去乙醯基酶抑制劑TSA有些微回復氯化鎳所減少的E-cadherin表現;同時蛋白酶體抑制劑MG132也降低氯化鎳所誘導的E-cadherin蛋白水解作用。因此,氯化鎳會透過ROS的活化、造成E-cadherin promoter高度甲基化、histone去乙醯基化和蛋白酶體的降解作用等,來減少E-cadheirn的表現。本研究發現鎳會誘導細胞進行上皮-間質轉換,這可能參與鎳所造成的組織纖維化和細胞癌化的過程。

Epithelial-mesenchymal transition (EMT) has been considered as a critical event in the pathogenesis of lung fibrosis and tumor metastasis. In EMT, the expression of differentiation markers switched from cell-cell junction proteins such as E-cadherin to mesenchymal markers including fibronectin and vimentin, and the mechanism underlying EMT involves coordination of multiple signaling pathways. Nickel containing compounds have been associated with lung carcinogenesis and other adverse health effects. However, the relationship between nickel and EMT in cells is not clear. This study mainly explored whether nickel affect the expression of gene durning EMT in humen bronchial epithelial cells. We also clarified the mechemisms of nickel chloride induced EMT. BEAS-2B cells were exposed to nickel compounds. E-cadherin and fibronectin expression levels were examined by RT-PCR and immunoblot. We found that nickel chloride induced the EMT phenotype markers alterations such as up-regulation of fibronectin and down-regulation of E-cadherin. The results of 1-D gel electrophoresis/SDS-PAGE indicated that nickel chloride decreased the expression of Annexin 2. The NF-κB inhibitor, BAY 11-7082, abolished the up-regulation of fibronectin induced by nickel chloride, but no effect in E-cadherin. Reactive oxygen species (ROS) inhibitor, DNA methyltransferase (DNMT) inhibitor, histone deacetylase (HDAC) inhibitor and proteasome inhibitor were used with folw cytometry and immunoblot to determine that mechanisms of nickel chloride regulated E-cadherin in BEAS-2B cells. The ROS inhibitor, N-Acetyl Cysteine (NAC), could block EMT and the expression of HIF-1α and LCN2 induced by nickel chloride. DNMT inhibitor, 5-aza-2’-deoxycytidine (5-Aza-dc), could restore the down-regulation of E-cadherin induced by nickel chloride. The hypermethylation of E-cadherin promoter was also induced by nickel chloride using methyl-specific polymerase chain reaction (MSP) to ditect. The HDAC inhibitor, trichostatin A (TSA), could slightly reverse the down-regulation of E-cadherin by nickel chloride. We also found that proteasome inhibitor, MG132, could diminish degradation of E-cadherin by nickel chloride. Our conclusion is that nickel chloride induced down-regulation of E-cadherin by possibly involving in ROS induction, hypermethylation in E-cadherin promoter, histone deacetylation and proteasome degradation. These findings demonstrate for the first time that nickel could induce EMT, which may participate in the processes of tissue fibrosis and carcinogenesis.

目錄
頁次
壹、 中文摘要 1
貳、 英文摘要 (Abstract) 2
叁、 縮寫表 4
肆、 緒論 (Introduction)
一、致癌性物質-鎳 6
二、鎳的暴露途徑 6
三、比較我國及世界各國對鎳的相關法規 7
四、抽菸與職業性暴露鎳皆會構成肺癌的危險上升 8
五、鎳對肺細胞的調控機制 9
1. 鎳的毒理機制模式 9
2. 鎳會造成DNA損傷以及降低解毒酵素Glutatione-S-transferase的表現 11
3. 鎳調控細胞中的表觀遺傳機制
(Epigenetic mechanisms) 12
4. 鎳啟動發炎反應來促進細胞增殖(proliferation) 12
5. 鎳造成肺部發生纖維化 13
六、細胞進行上皮-間質轉換過程
(epithelial-mesenchymal transition, EMT)之介紹
13
1. 上皮細胞的適應性 13
2. EMT的分類 14
3. EMT的生物標記(Biomarkers) 14
七、肺纖維化、肺癌及EMT的相關性 18
伍、 研究動機 (Motive) 20
陸、 實驗材料與方法 (Materials and methods)
一、 材料
1. 人類肺細胞株(cell line)之來源 21
2. 藥品試劑 (drug and reagent) 21
3. 實驗設備 (instruments) 25
二、 方法
1. 細胞培養 (cell culture)
1-1. 細胞培養 (cell culture) 26
1-2. 繼代培養 (replate cell) 26
1-3. 冷凍細胞 (frozen cell) 26
1-4. 解凍細胞 (defrozen cell) 27
2. PCR產物的接合反應 (ligation reaction) 27
3. 轉形作用 (transformation)
3-1 勝任菌體(competent bacterial cells)之製備 28
3-2 轉形作用之步驟 28
4. 抽取中量質體DNA (midi preparation of plasmid DNA) 29
5. 細胞質體轉染 (transfection) 30
6. Lcuiferase assay (reporter assay)
6-1. β-galactosidase的活性測定 30
6-2. Luciferase的活性測定 31
7. 西方墨點法 (western blot)
7-1. 樣品製備 (sample preparation) 32
7-2. 蛋白濃度定量分析 (protein quantification) 32
7-3. SDS-聚丙烯醯胺板膠電泳(SDS-PAGE)之轉漬 33
7-4. 抗體作用及偵測方法
(antibody hybridization and detection) 34
8. RNA萃取(extraction)與反轉錄聚合酶連鎖反應
(reverse transcription and polymerase chain
reaction, RT-PCR)
8-1. RNA萃取 35
8-2. cDNA的合成 (synthesis of cDNA) 36
8-3. 聚合酶鏈鎖反應
(polymerase chain reaction, PCR) 36
9. 凝膠洋菜瓊脂 (agarose gel)得電泳分析
9-1. 1.5 % agarose gel的製備方法 36
9-2. 電泳操作 36
10. DNA甲基化專一性的聚合酶連鎖反應
10-1. genomic DNA的純化 37
10-2. MSP (methylation-specific PCR) 37
11. ROS生成之測定
11-1. 細胞染色 39
11-2. 儀器操作與軟體分析 39
12. 免疫螢光染色法(immunofluorescence staining) 40
13. RNA干擾 (RNAi) 40
13-1. 抽取質體與培養病毒 41
13-2. 病毒濃度測定 41
13-3. Lentivirus shRNA infection of cell 41
14. EMSA (Electrophoretic mobility shift assay)
14-1. 核蛋白萃取 (nuclear protein extraction) 42
14-2. EMSA之步驟 42
15. Chromatin immunoprecipitation assay (ChIP) 43
柒、 結果 (Results)
一、鎳誘使BEAS-2B細胞發生EMT現象 46
二、、氯化鎳(NiCl2)影響EMT生物標記的作用機轉 50
1. 氯化鎳不會透過游離鐵來造成BEAS-2B細胞進行
EMT 51
2. 氯化鎳部分影響E-cadherin蛋白質的穩定性 51
3. 氯化鎳活化BEAS-2B細胞中的ROS,進而影響下游訊息路徑來參與細胞的EMT
52
4. 氯化鎳影響BEAS-2B細胞染色質的histone修飾 53
5. 氯化鎳提高E-cadherin promoter的甲基化而減少E-cadherin表現 53
捌、 討論 (Dicussion) 56
玖、 圖表說明 (Figures)
Fig. 1. 重金屬誘導BEAS-2B細胞進行EMT 62
Fig. 2. 氯化鎳影響EMT標記mRNA表現 63
Fig. 3. 低劑量氯化鎳長時間處理BEAS-2B細胞的影響 64
Fig. 4. 較低劑量氯化鎳長時間暴露細胞的影響 65
Fig. 5. 氯化鎳不影響E-cadherin mRNA的穩定性 66
Fig. 6. 氯化鎳減少E-cadherin promoter的活性 67
Fig. 7. 氯化鎳對E-cadherin的轉錄因子 mRNA之影響 68
Fig. 8. EMSA分析蛋白與E-cadherin promoter的結合 69
Fig. 9. ChIP分析Slug與E-cadherin promoter的結合 70
Fig. 10. 運用共軛交顯微鏡觀察細胞的E-cadherin表現 71
Fig. 11. 一維電泳分析BEAS-2B細胞的蛋白變化 72
Fig. 12. 氯化鎳減少Annexin2的表現量 73
Fig. 13. NF-κB與氯化鎳所誘導的EMT之相關性 74
Fig. 14. 游離鐵不參與氯化鎳所誘導的EMT 75
Fig. 15. 氯化鎳對於E-cadherin蛋白穩定性之影響 76
Fig. 16. 氯化鎳誘使BEAS-2B細胞產生ROS 77
Fig. 17. ROS參與氯化鎳所誘導的EMT 78
Fig. 18. 氯化鎳影響histone的去乙醯基化 79
Fig. 19. 氯化鎳影響基因甲基化,使E-cadherin表現減少 80
Fig. 20. 氯化鎳造成E-cadherin promoter高度甲基化 81
Fig. 21. 氯化鎳對於DNA甲基轉移酵素mRNA的影響 82
Fig. 22. 氯化鎳對BEAS-2B shDNMT1細胞之影響 83
Fig. 23. 氯化鎳誘導細胞進行EMT的分子機制 84
拾、 參考文獻 (Reference) 85
拾壹、 附表及附圖
附表1 引子序列及上機條件 98
附表2 E-cadherin promoter的MSP引子序列 99
附表3質譜儀偵測蛋白之結果 100
附圖1 The gene map of E-cadherin promoter (-178~+92) plasmid 101

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