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研究生:楊敏潔
研究生(外文):Min-Chieh Yang
論文名稱:探討活化態Notch1受體所誘導COX-2之基因表現於胃癌形成過程中所扮演的角色
論文名稱(外文):Effects of COX-2 expression induced by the activated Notch1 receptor on gastric cancer progression
指導教授:葉添順
指導教授(外文):Tien-Shun Yeh, Ph. D.
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:86
中文關鍵詞:Notch1受體環氧化酶胃癌
外文關鍵詞:Notch1 receptorCOX-2gastric cancer
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胃癌是常見的胃部腫瘤,而其中超過90 %胃癌屬於胃腺癌。根據世界衛生組織2009年2月的報導,統計2004年癌症死亡排名上,胃癌是癌症死亡排名的第二名,死亡人數達80萬人。在台灣,胃癌於民國九十五年是癌症致死率中的第七名。由於胃癌早期症狀不明顯,因此被診斷出來經常已經為中後期癌症,故胃癌之癒後極差,而在過去的研究指出,胃癌較有效之治療方式乃是手術切除。因此早期診斷治療及更進一步分析了解造成胃癌的分子機轉是極需更深入探討的領域。
Notch的訊息傳遞路徑已經被廣為熟知,而在許多組織中扮演了重要之角色,例如在神經形成、血管形成,甚至免疫系統的形成過程中,Notch的訊息傳遞路徑都扮演重要的地位,而也有研究指出Notch的訊息傳遞路徑在腸胃道中可維持細胞處於未分化的狀態,亦可微調細胞的命運決定或分化路途。在不同癌症形成的過程中,Notch的訊息傳遞路徑可做為致癌的或抑癌的角色。由實驗室先前的研究顯示:胃癌病人在表現Jagged1這個Notch ligand的情況下,其癌症存活率會比沒有表現的病患來的低。而且同時也發現活化態Notch1受體確實可促進胃癌細胞癌化之能力;當使用COX-2抑制劑的情況下,則會抑制活化態Notch1受體所促進胃癌細胞癌化之能力。因此本論文將進一步探討活化態Notch1受體是否會透過COX-2,進而影響胃癌之癌化能力。
本論中首先使用會持續表現活化態Notch1受體之SC-M1胃癌細胞株SC-M1/HA-N1IC #4、#7和#12,並証明在這些細胞株中,Notch1下游之訊息傳遞路徑有活化的情形。此外更進一步的証實活化態Notch1受體可能會透過CBF1 所媒介之訊息路徑,藉此活化COX-2啟動子的活性,並進而促使COX-2之mRNA和蛋白表現量增加。本論文之研究也同時發現:在削弱SC-M1/HA-N1IC #7細胞株之COX-2表現的情形下,由活化態Notch1受體所促進聚落形成、細胞移動和細胞侵襲能力皆會被抑制,但若削弱COX-1表現則不會有此現象發生。
同樣以反證的方式證明,不論是以siRNA的方法抑制內生性Notch1受體的表現,亦或是使用γ-secretase抑制劑DAPT,抑制Notch訊息傳遞路徑的情況下,COX-2蛋白的表現量皆有下降的情形。接著在削弱SC-M1胃癌細胞內生性之Notch1受體的情況下,不論是表現COX-2,亦或是以PGE2處理皆會回復胃癌細胞的聚落形成、細胞移動和細胞侵襲之能力。綜合以上結果,推測活化態Notch1訊息路徑有可能部份透過COX-2,進而促進胃癌之癌化過程。
Gastric carcinoma (GC) is the most frequent malignant neoplasm of the stomach, with adenocarcinoma accounting for more than 90% of all carcinomas. It is the second cancer death ranked in the world, and the seventh most common cancer-related cause of death in Taiwan. At present, curative surgery remains the most effective treatment, but prognosis remains poor because most patients have advanced disease at diagnosis. Therefore, it is important to gain a further understanding of the biology of GC and the genetic alterations underlying this malignancy.
The Notch signaling pathway is known to regulate numerous tissues formation, such as neurogenesis, angiogenesis, and the immune system, to maintain cells in an undifferentiated state, and to control cell fate and differentiation. Notch signaling is oncogenic and tumor suppressive in a variety of human tumors. Base on previous studies, expression of Notch ligand Jagged1 is correlated with aggressiveness of human gastric cancer. Patients with Jagged1 expression in gastric cancer tissues have a poor survival rate. The activated Notch1 receptor can promote the colony-forming ability of SC-M1 gastric cancer cells. On the contrary, COX-2 inhibitor NS-398 is able to suppress colony-forming ability which is promoted by the activated Notch1. In this study, whether the activated Notch1 receptor can induce gastric cancer progression of SC-M1 cells through COX-2 is evalated.
The constitutively expressing Notch1 receptor intracellular domain (N1IC) in SC-M1 gastric cancer cells activates expression of downstream targets of Notch signaling. Furthermore, Notch1 signaling elevates COX-2 expression in SC-M1 cells and both N1IC and C promoter-binding factor 1 (CBF1) bind to COX-2 promoter. We also find that the Notch1 signaling-enhanced tumor progression is suppressed by COX-2 knockdown in SC-M1 cells.
Additionally, knockdown Notch1 and use γ-secretase inhibitor DAPT decline the COX-2 expression in SC-M1. Tumor progression inhibited by Notch1 knockdown is restored by prostaglandin E2 or exogenous COX-2 in SC-M1 cells. Taken together, these results suggest that activating Notch1 signal pathway promotes gastric cancer progression, at least in part through COX-2.
目 錄
縮寫表……………………………………………………………………………. 4
壹、 中文摘要……………………………………………………………………. 6
英文摘要…………………………………………………………………………. 8
貳、 緒論…………………………………………………………………………. 10
ㄧ、胃癌……………………………………………………………………. 10
二、Notch訊息傳遞路徑…………………………………………………... 12
三、Cyclooxygenase-2……………………………………………………… 15
四、研究構想……………………………………………………………….. 17
參、 研究材料與方法…………………………………………………………….. 18
<材料>
ㄧ、細胞株………………………………………………………………….. 18
二、藥品、試劑與緩衝液………………………………………………….. 18
三、抗體……………………………………………………………………... 23
四、質體…………………………………………………………………….. 24
<方法>
ㄧ、細胞培養………………………………………………………………… 25
二、暫時轉染…………………………………………………………..…… 27
三、西方點墨法……………………………………………………………... 27
四、即時定量聚合酶鏈鎖反應……………………………………………… 29
五、冷光報導分析…………………………………………………………… 31
六、染色質免疫沉澱分析法………………………………………………… 32
七、細胞聚落培養分析…………………………………………………….. 34
八、細胞移動與侵襲能力分析實驗………………………………………… 34
肆、 實驗結果
一、在持續表現Notch1受體之SC-M1胃癌細胞中,其Notch1受體的下游基因之mRNA和蛋白表現皆有上升的情形………………………… 37
二、活化態Notch1受體會調控COX-2 啟動子,促進COX-2之mRNA和蛋白之表現………………………………………………………….… 37
三、活化態Notch1受體透過CBF1 所媒介的路徑調控COX-2 啟動子… 38
四、活化態Notch1受體與CBF1會結合在COX-2啟動子上…………… 39
五、COX-1抑制劑valeryl salicylate並不會影響活化態Notch1受體所促進之聚落形成、細胞移動和細胞侵襲的能力………..………………… 40
六、削弱 (knockdown)COX-2之表現,可以抑制活化態Notch1受體所促進癌化之能力;但削弱COX-1之表現卻不會有此影響……………… 40
七、以γ-secretase抑制劑DAPT處理或表現Notch1的shRNA抑制SC-M1胃癌細胞COX-2蛋白質表現………………………………………… 41
八、表現COX-2或PGE2皆會回復因削弱內生性Notch1受體所造成抑制SC-M1胃癌細胞癌化之能力………………………………………… 42
九、COX-2抑制劑 (NS-398)或γ-secretase抑制劑 (DAPT)會抑制SC-M1胃癌細胞癌化的能力;然而同時處理這兩個藥物並未加強抑制效果.... 43
十、活化態Notch1受體會促進AGS和KATO III胃癌細胞癌化之能力.... 43
十一、削弱c-Myc會抑制Notch1受體對SC-M1胃癌細胞之癌化能力的提升作用……………………………………………………………….…... 44
伍、 討論……………………………………………………………….…................ 45
陸、 參考文獻………………………………………………………….…................ 49
柒、 圖例……………………………………………………………….…................ 67
陸、參考文獻
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