臺灣博碩士論文加值系統

上皮細胞鈣黏蛋白 (E-cadherin) 是一種上皮細胞間的連接蛋白，在正常細胞中，主要負責調控細胞間的緊密連接。E-cadherin會藉由與p120 catenin和β-catenin的結合，間接與細胞結構蛋白相連接，並參與多種訊息傳遞路徑。研究發現細胞要移行時，E-cadherin的表現量會受到轉錄調控或蛋白酶的酶切而降低其在細胞中的表現。E-cadherin會被γ-secretase酶切並釋放細胞質片段，稱作上皮細胞鈣黏蛋白的細胞質片段2 (E-cad/CTF2)。有研究指出，E-cad/CTF2會參與轉錄因子kaiso所進行的轉錄調控，但E-cad/CTF2是否影響細胞生長、爬行及凋亡，尚不清楚。先前實驗室研究發現，E-cad/CTF2會與參與長鏈脂肪酸β-oxidation的粒線體蛋白HADHA有交互作用；並找尋可能被E-cad/CTF2調控的基因。由本論文研究，我們發現E-cad/CTF2可能會促進細胞爬行，並促使HeLa細胞抵抗多柔比星 (doxorubicin) 所引發的細胞凋亡。藉由duo-link實驗顯示E-cad/CTF2與HADHA的交互作用，會存在於粒線體和細胞質中；並分析細胞中NAD+/NADH的比例及ATP的含量，E-cad/CTF2的表現似乎不影響HADHA的活性。在穩定表現E-cad/CTF2的HeLa細胞株中，以siRNA降低HADH表達，E-cad/CTF2的抗細胞凋亡的能力不受影響。因此我們認為，HADHA與E-cad/CTF2在doxorubicin所引發的細胞凋亡有各自的角色。此外，藉由逆轉錄聚合酶連鎖反應驗證了一種位於內質網膜上的stearoyl-CoA去飽和酶，SCD5，其mRNA表現量在E-cad/CTF2表現時會下降。由啟動子的報導實驗，我們並沒有找到E-cad/CTF2在SCD5啟動子的調控區域，但以siRNA 降低β-catenin表達時，SCD5的mRNA同樣也下降。綜合以上所述，我們發現E-cadherin被酶切後產生的片段E-cad/CTF2，可促進細胞爬行與doxorubicin抗藥性，並藉由與HADHA的蛋白交互作用或是對SCD5的轉錄調控，參與脂肪酸的代謝。

E-cadherin is an epithelial cell-cell adhesion protein mediating normal epithelial cell contacts. It links to cellular structure proteins and involves in cellular signal transduction pathways through the association with p120 catenin and -catenin. Many studies have revealed that E-cadherin might be down-regulated by transcriptional repression or proteolytical degradation while the cells start to migrate. The proteolytical cleavage of E-cadherin mediated by γ-secretase and releases the E-cadherin C-terminal fragment 2 (E-cad/CTF2). It has been shown that E-cad/CTF2 is involved in kaiso-mediated transcriptional regulation. However, the roles of E-cad/CTF2 in cell growth, migration and apoptosis are still unclear. From the previous laboratory studies, E-cad/CTF2 interacts with HADHA which is a mitochondrial protein involved in β-oxidation of long-chain fatty acids and discovered the differentially expressed genes regulated by E-cad/CTF2. In this thesis, we demonstrated that E-cad/CTF2 could promote HeLa cell migration and enable the cell against apoptosis induced by doxorubicin treatment. We confirmed the mitochondrial and cytosol interaction between E-cad/CTF2 and HADHA by duo-link assays. However, the expression of E-cad/CTF2 had no effects on the ratio of intracellular NAD+/NADH and the level of ATP. Knockdown of HADHA expression in HeLa E-cad/CTF2 stable cell line did not abolish the anti-apoptosis effect of E-cad/CTF2. Thus, the mechanism of E-cad/CTF2 against doxorubicin-induced apoptosis might be independent from HADHA. Moreover, we confirmed that the expression of E-cad/CTF2 could down-regulate the SCD5 by RT-qPCR. SCD5 is a stearoyl-CoA desaturase located in the membrane of endoplasmic reticulum. We did not identify the E-cad/CTF2 response elements in SCD5 promoter by reporter assay. But, knockdown of β-catenin expression was involved in the down-regulation of SCD5 mRNA. Taken together, our studies reveal the cleavage of E-cadherin might promote cell migration and doxorubicin resistance by E-cad/CTF2. E-cad/CTF2 might be involved in fatty acid metabolism through interacting with HADHA or regulating SCD5 expression.

目錄
指導教授推薦書………………………………………………………..…
論文口試委員會審定書………………………………………………..…
致謝……………………………………………………………………..ⅲ
中文摘要………………………………………………………………...ⅳ
Abstract …………………………………………………………………ⅵ
目錄……………………………………………………………………...ⅷ
圖目錄…………………………………………………………………. .xi
表目錄………………………………………………………………….xiii
縮寫表………………………………………………………………….xiv
第一章 緒論……………………………………………………………...1
1.1 E-cadherin在正常細胞中的角色………………………………1
1.2 E-cadherin與癌症生成的關係…………………………………3
1.3 發現E-cadherin 在癌細胞核中………………………………..3
1.4 可能受到E-cad/CTF2調控的基因SCD5………………………5
1.5 與E-cad/CTF2結合的新蛋白HADHA………………………...6
1.6 實驗目的………………………………………………………...8
1.7 實驗設計………………………………………………………...9
第二章 實驗方法與材料……………………………………………….12
2.1 細胞培養……………………………………………………….12
2.2 細胞轉染 (Transfection) ……………………………………...12
2.3 質體建構 (plasmid) …………………………………………..12
2.4 siRNA ………………………………………………………….13
2.5 篩選穩定細胞株…………………………………………….…14
2.6 蛋白質的製備…………………………………………………14
2.7 西方墨點法 (Western blot) …………………………………..14
2.8 萃取mRNA及RT-qPCR ………………………………….....15
2.9 MTT assay …………………………………………………….15
2.10 細胞群落形成實驗 (Colony formation) ……………………...16
2.11 細胞遷移實驗 (Migration) …………………………………...16
2.12 Annexin V-FITC/ SYTOX green assay ………………………..16
2.13 Duo-link assay …………………………………………………17
2.14 粒線體追蹤染劑 (MitoTracker) ……………………………...18
2.15 免疫螢光染色 (Immunofluorescence staining) ………………18
2.16 細胞質/粒線體分離……………………………………………18
2.17 NAD+/ NADH assay …………………………………………..19
2.18 ATP assay ……………………………………………………...19
2.19 Reporter assay …………………………………………………20
2.20 統計分析……………………………………………………….20
第三章 實驗結果
3.1 探討E-cad/CTF2及全長的E-cadherin在細胞中之功能……..21
3.2 探討E-cad/CTF2與HADHA在doxorubicin抗性中的關係…22
3.3 探討HADHA在細胞中之功能………………………………25
3.4 根據cDNA array的結果找尋可能受到E-cad/CTF2調控的基
因………………………………………………………………25
3.5 探討p120、Kaiso及β-catenin對SCD5之基因調控………26
第四章 討論……………………………………………………………28
4.1 探討E-cad/CTF2對細胞的生長、爬行與doxorubicin抗性之影
響………………………………………………………………27
4.2 探討全長E-cadherin在細胞生長、爬行與doxorubicin抗性中的角色…………………………………………………………30
4.3 探討E-cad/CTF2與HADHA在doxorubicin抗性中之關係…30
4.4 探討HADHA在細胞中之功能………………………………32
4.5 探討E-cad/CTF2對SCD5之基因調控………………………33
參考文獻………………………………………………………………...36
圖表……………………………………………………………………...44
附錄……………………………………………………………………...70

圖目錄
圖一、探討 E-cad/CTF2 在癌細胞中的功能之流程圖………………44
圖二、於HeLa細胞株轉染表現E-cad/CTF2之質體並觀察E-cad/CTF2對細胞生長之影響……………………………………………..45
圖三、以表現E-cad/CTF2質體轉染以及穩定表現的細胞株觀察
E-cad/CTF2對細胞爬行之影響……………………………….47
圖四、以表現E-cad/CTF2之質體轉染以及穩定表現的細胞株觀察
E-cad/CTF2對doxorubicin引發的細胞凋亡之影響…………49
圖五、以流式細胞儀分析穩定表現E-cad/CTF2的HeLa細胞株對
doxorubicin引發的細胞凋亡之影響…………………………...50
圖六、以西方墨點法分析穩定表現E-cad/CTF2的細胞株對doxorubicin
引發的細胞凋亡之影響………………………………………..52
圖七、以穩定表現E-cadherin之細胞株觀察E-cadherin對細胞生長、爬行之影響……………………………………………….…….53
圖八、以穩定表現E-cadherin之細胞株觀察E-cadherin對doxorubicin
引發的細胞凋亡之影響………………………………………..56
圖九、以Duo-link驗證E-cad/CTF2和HADHA的蛋白交互作用…57
圖十、以Duo-link與Mitotracker確認E-cad/CTF2和HADHA在細
胞中交互作用之位置…………………………………………..58
圖十一、以西方墨點法與MTT分析HADHA對E-cad/CTF2的蛋白表
現量與doxorubicin抗性之影響……………………………….59
圖十二、分析E-cad/CTF2對HADHA、HADHB的蛋白表現及NAD+/
NADH比例、ATP含量之影響………………………………...60

圖十三、以siRNA knockdown HADHA觀察細胞的生長、爬行及doxorubicin處理下的存活率之影響…………………………61
圖十四、以RT-qPCR觀察E-cad/CTF2對SCD5 mRNA表現量之影響………………………………………………………………63
圖十五、利用reporter assay觀察E-cad/CTF2對SCD5 promoter之影
響………………………………………………………………64
圖十六、以RT-qPCR觀察β-catenin、p120及Kaiso對SCD5 mRNA
表現量之影響…………………………………………………66
圖十七、以穩定表現E-cad/CTF2的HeLa及MCF-7細胞株觀察E-cad/CTF2對細胞生長之影響………………………………67
圖十八、E-cad/CTF2的功能性探討之模型圖…………………………68
附圖一、E-cadherin被酶切的位點及相對應的片段…………………70
附圖二、利用Gal4-reporter assay發現E-cad/CTF2具有轉錄活化的活
性………………………………………………………………71
附圖三、利用 cDNA array 分析找尋可能被E-cad/CTF2 調控的目標
基因……………………………………………………………72
附圖四、利用MALDI-TOF尋找並以GFP-Trap確認E-cad/CTF2與HADHA之交互作用…………………………………….……73

表目錄
表一、以RT-qPCR驗證cDNA array 所分析的可能受E-cad/CTF2 調
控之目標基因……………………………………………………..69

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