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研究生:曾芸倩
研究生(外文):Yun-Chien Tseng
論文名稱:探討活化態Notch2受體在胃癌形成過程中所扮演的角色
論文名稱(外文):Roles of the activated Notch2 receptor in gastric cancer progression
指導教授:葉添順
指導教授(外文):Tien-Shun Yeh
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:解剖暨細胞生物學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:109
中文關鍵詞:Notch2受體
外文關鍵詞:Notch2EMT
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胃癌是世界上常見且具有致死性的疾病之一,早期診斷不易,所以預後並不理想。研究指出cyclooxygenase 2 (COX-2)的表現與人類胃腺癌的浸潤胃壁深度、淋巴腺擴散、淋巴結轉移及癒後差有關,且胃癌細胞有上皮間質化(epithelial to mesenchymal transition, EMT)的現象,藉由降低細胞間的附著,使癌細胞移動性及侵略能力增加。Notch訊息傳遞路徑對於決定細胞命運扮演重要的角色,例如細胞生長、細胞分化、細胞凋亡…等等,且活化的Notch受體在不同癌細胞中,可能是致癌基因或抑制腫瘤因子,進而影響腫瘤生成。在胚胎發育及腫瘤生成時,活化的Notch訊息傳遞路徑皆會參與EMT。目前對於胃癌發生的機轉尚未明瞭,所以本論文探討活化態Notch2受體調控胃癌癌化過程的機轉,為了探討胃癌形成過程中,Notch2訊息傳遞路徑所扮演的角色,本論文首先在SC-M1胃癌細胞株中,建立了會持續大量表現活化態Notch2受體的細胞株(SC-M1/myc-N2IC-His)和持續抑制內生性Notch2受體的細胞株(SC-M1/Notch2i) 。研究結果顯示活化態Notch2受體的表現會促進胃癌細胞的生長,且增加胃癌細胞群落形成、移動和侵襲的能力。而抑制內生性Notch2受體則會抑制胃癌細胞的生長、胃癌細胞群落形成、移動和侵襲的能力。在持續大量表現活化態Notch2受體的細胞株中,其細胞型態較為狹長;而抑制內生性Notch2受體的細胞株中,其細胞型態則較為立方,顯示活化態Notch2受體會影響EMT的現象。這些結果顯示,活化的Notch2訊息傳遞路徑確實會調控胃癌形成的過程。進一步發現在SC-M1細胞中表現活化態Notch2受體會增加COX-2的表現,而且抑制COX-2的活性或表現量皆會降低原本活化態Notch2受體所導致細胞型態的改變及腫瘤生成的促進,相反地,在SC-M1胃癌細胞中抑制內生性Notch2受體則會抑制COX-2的表現,且大量表現COX-2會促進原本抑制內生性Notch2受體所導致腫瘤生成的抑制並使細胞型態較為拉長。此外,本論文也證實活化態Notch2受體會結合在COX-2啟動子上,活化COX-2啟動子的活性調控COX-2的表現,進而影響胃癌細胞群落形成、移動和侵襲的能力。綜合以上結果,活化態Notch2受體會藉由調控COX-2的表現而影響胃癌形成的過程。
Gastric carcinoma is one of the most common malignancies worldwide. Diagnosis of the early-stage gastric cancer is difficult, so it always has poor outcome. COX-2 expression is correlated with depth of invasion, lymphatic vessel invasion, lymph node metastasis, and poor prognosis of human gastric carcinoma. In gastric cancer cells with fibroblastoid morphological changes, activation of epithelial to mesenchymal transition (EMT) signaling was suggested to promote motility and invasiveness through decreasing cell-cell adhesion. The activation of Notch signal pathway participates in EMT in development and tumorigenesis. The Notch signaling pathway plays an important role in cell fate determination, differentiation, proliferation, apoptosis. The activated Notch receptor could be oncogenic or tumor suppressive to modulate tumorigenesis. However, the mechanism of gastric carcinoma progression is not clear until now. To study role of Notch2 signaling in tumor progression of SC-M1 cells, Notch2 receptor intracellular domain (N2IC)-expressing cells (SC-M1/myc-N2IC-His) and Notch2-knockdown cells (SC-M1/Notch2i) were established in the present study. We showed that cell proliferation of SC-M1 gastric cancer cells was increased by the expression of N2IC, the activated form of Notch2 receptor. The activated Notch2 receptor raised the colony-forming, migration and invasion abilities of SC-M1 cells. The knockdown of endogenous Notch2 receptor inhibited cell proliferation, colony-forming, migration and invasion abilities. Overexpression of N2IC exhibited fibroblastoid morphological change and knockdown of endogenous Notch2 receptor exhibited cuboidal-like morphological change in SC-M1 cells. Additionally, N2IC increased the expression of COX-2. The fibroblastoid morphological change induced by N2IC was attenuated after treatment with COX-2 inhibitor, NS-398 in SC-M1 cells. NS-398 inhibited colony-forming、migration and invasion abilities enhanced by N2IC. COX-2 knockdown inhibited colony-forming、migration and invasion abilities enhanced by N2IC. Knockdown of Notch2 receptor repressed COX-2 expression. PGE2 restored migration and invasion abilities suppressed by knockdown of endogenous Notch2 receptor in SC-M1 cells. Exogenous COX-2 restores migration and invasion abilities suppressed by knockdown of endogenous Notch2 receptor in SC-M1 cells. We also found that N2IC bound to COX-2 promoter and enhanced the COX-2 promoter activity to regulate the expression of COX-2. Furthermore, N2IC regulated colony-forming, migration and invasion abilities through COX-2. These results suggest that Notch2 signaling is critical for promotion of tumor progression in gastric cancer cells by up-regulating COX-2 expression.
縮寫表…………………………………………………….………………………….2
中文摘要……………………………………………………………………………..5
英文摘要……………………………………………………………………….…….7
目錄…………………………………………………………………………..………9
圖目錄………………………………………………………………………….…….12
第一章 前言……………………………………………… ……………..………...14
一、胃癌………………………………………………………………………..14
二、Notch受體結構及訊息路徑………………………………………………15
三、上皮間質化(epithelial to mesenchymal transition, EMT)…………….…..18
四、研究動機與構想…………………………………………………………..19
第二章 研究材料與方法…………………………………….………………….…21
<材料>
一、細胞株………………………………………………………………….….21
二、質體………………………………………………………………….…….21
三、抗體…………………………………………………………………….….22
四、藥品與藥物……………………………………………………………… .24
五、材料與儀器……………………………………………………………… .26
<方法>
一、 建立穩定細胞株…………………………………………………………..27
二、 細胞生長計數……………………………………………………………..28
三、 細胞存活率分析法………………………………………………………..28
四、 流式細胞儀分析法………………………………………………………..28
五、 細胞群落培養分析法……………………………………………………..29
六、 裸鼠皮下注射腫瘤分析法………………………………………………..30
七、 細胞爬移分析法………………………………………………………….30
八、 細胞侵入分析法………………………………………………………….30
九、 西方點墨法……………………………………………………………….31
十、 細胞冷凍………………………………………………………………….34
十一、細胞解凍……………………………………………………………….34
十二、反轉錄聚合酵素鏈鎖反應…………………………………………….34
十三、即時定量聚合酵素鏈鎖反應………………………………………….35
十四、傷口癒合分析法……………………………………………………….36
十五、免疫螢光染色法……………………………………………………….36
十六、染色質免疫沉澱分析法……………………………………………….37
十七、螢光報導分析法……………………………………………………….39
第三章 結果
一、在SC-M1胃癌細胞中建立會持續大量表現活化態Notch2受體的細胞株……………………………………………………………….….…….40
二、在SC-M1胃癌細胞中大量表現活化態Notch2受體會促進腫瘤細胞生長………………………………………………………………….…..…41
三、在SC-M1胃癌細胞中大量表現活化態Notch2受體促進腫瘤生成的過程…………………………………………………………………...……42
四、在SC-M1胃癌細胞中抑制內生性Notch2受體的表現會抑制腫瘤生成………………………………………………………………….…..….43
五、活化態Notch2受體的表現會影響SC-M1胃癌細胞的細胞型態….....44
六、大量表現活化態Notch2受體會增加SC-M1胃癌細胞內COX-2的表現而促進腫瘤生成…………………………………………………….…...45
七、持續抑制內生性Notch2受體表現會抑制SC-M1胃癌細胞中COX-2的表現而影響腫瘤生成的過程……………………………………….…...47
八、活化態Notch2受體會結合並活化COX-2啟動子…………………......48
第四章 討論……………………………………………………………………..50
第五章 參考文獻………………………………………………………………. 54
第六章 圖表與圖表說明…………………………………………………..........69
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