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研究生:柯家錚
研究生(外文):Chia-Cheng Ko
論文名稱:以蛋白質體學方法研究幽門螺旋桿菌感染胃腺癌細胞的致癌機轉
論文名稱(外文):Proteomics analysis of Helicobacter pylori mediated carcinogenesis in gastric adenocarcinoma cells
指導教授:周綠蘋周綠蘋引用關係
指導教授(外文):Lu-Ping Chow
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生物化學暨分子生物學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:83
中文關鍵詞:蛋白質體學幽門螺旋桿菌致癌機轉
外文關鍵詞:Helicobacter pyloricarcinogenesisproteomics
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過去五十年來,胃癌是世界上最常發生的癌症之ㄧ,在所有癌症造成的死亡中,高居第二名。胃癌發生的過程通常是長期的慢性發炎,慢慢導致細胞的萎縮和化生,然後走向癌化。而胃部的慢性發炎,最普遍的原因是幽門螺旋桿菌的感染,根據流行病學調查和動物實驗的證實,幽門螺旋桿菌長期感染之下確能造成胃癌的形成,所以在1994年世界衛生組織即定義幽門螺旋桿菌為第一型致癌物。
幽門螺旋桿菌感染可造成胃炎、消化性潰瘍和胃癌等不同程度的疾病,所以幽門螺旋桿菌感染或雪|產生”disease-specific”的反應,所以本篇研究即在探討幽門螺旋桿菌感染胃腺癌上皮細胞,所造成的蛋白質表現差異,希望能找到幽門螺旋桿菌導致胃癌的關鍵蛋白質。

過去的研究指出,幽門螺旋桿菌感染胃上皮細胞後會引發細胞的發炎反應,像是IL-8、IL-1、TNF-ㄤ必茩M激素表現量上升,以及Cyclooxygenase 2 (COX-2)、inducible Nitric Oxide Synthase (iNOS)的活化,而這些蛋白質的持續表現已知會促使細胞增生、減緩細胞凋亡、增加細胞DNA突變可能性,因此增加了細胞癌化的機會。在本實驗中,為檢視幽門螺旋桿菌感染胃上皮細胞的效力,我們也測定了受感染細胞的IL-8、COX-2、iNOS。在確定了幽門螺旋桿菌染的有效性,即將感染的細胞進行細胞與細菌分離的步驟,以避免受細菌蛋白質的干擾,然後利用二維電泳展開蛋白質,將有感染與未感染幽門螺旋桿菌的細胞蛋白質進行表現量上的比較,選擇表現量有兩倍變化以上的蛋白質,利用基質輔助雷射脫附游離/ 飛行時間質譜分析(MALDI-TOF MS)做蛋白質鑑定。

鑑定到的蛋白質共有25個,其中24個表現量上升兩倍以上,包括了laminin B2、laminin biding protein、ERO1-like、villin 2、TCP-1、ubiquitin activating enzyme E1…等等,經由生物資訊學的統計分析,發現這些蛋白質其中已知和細胞的血管新生、細胞防禦、細胞骨架的重新生成以及細胞內蛋白質分解有關聯,這些蛋白質的表現可能是細胞受到幽門螺旋桿菌感染所呈現的壓力反應,也可能是細胞接收了幽門螺旋桿菌改變細胞骨架的訊息,所反應出的蛋白質變化。

整體而言,這些表現量有差異的蛋白質,提供了我們一個很好的資訊,可以藉此一窺幽門螺旋桿菌初始致病的可能機制,而一旦確立這些蛋白質致癌的有效性,或陶o些蛋白質將可作為疾病預後的指標。
During the last 50 years, gastric cancer ranks as one of the most frequent cancers and the second leading cause of cancer death. Gastric cancer usually arises in chronic stomach inflammation and where atrophy and intestinal metaplasia have supervened. The commonest cause of gastric inflammation is infection with Helicobacter pylori. It had been proved that consistent infection of Helicobacter pylori in stomach can cause gastric cancer; therefore Helicobacter pylori was defined as a carcinogen at WHO in 1994. H.pylori infection leads to gastritis, peptic ulceration and gastric adenocarcinoma. Moreover, H.pylori may induce disease-specific protein expression in gastric epithelial cells. The present study was aimed at determining differentially expressed proteins in H.pylori-infected gastric epithelial AGS cells and expected to find out the mediators in gastric carcinogenesis.

According to previous reports, the pathogenic mechanisms of H.pylori infection include the initiation and continuance of an inflammatory response (IL-8, IL-1 TNF-? and activation of Cyclooxygenase 2(COX-2) and inducible Nitric Oxide Synthase (iNOS). Continuous expression of these proteins would promote DNA damage and proliferation of gastric cells, then increase the risk of gastric carcinogenesis. To study the effects of H.pylori infection, our results show infection induces IL-8 release and up-regulation of COX-2 and iNOS expression in AGS cells.

AGS cells were treated with H.pylori at a MOI of 100 for 24 hr. To avoid the contamination of H.pylori proteins, AGS cells were collected and fractionated. The changes of protein patterns as separated by using two-dimensional electrophoresis and differentially expressed proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the peptide digestion. Twenty-five differentially expressed proteins, which the protein expression levels were increasing or decreasing by more than two-fold in H. pylori-infected cells, were analyzed. By the way of bioinformatics, these proteins (laminin B2, laminin binding protein, ERO1-like, villin 2, TCP-1 alpha, ubiquitin activating enzyme E1…) are documented to be related to the cell angiogenesis, cell-protection, cytoskeleton biogenesis, and protein degradation, and may also be mediated by cellular stress and stimuli from H. pylori infection, such as the reactive oxygen species and the signals of cytoskeleton rearrangement.

In conclusion, the identification of these differentially expressed proteins provide the valuable information for the better understanding of the pathophysiologic molecular mechanisms underlying H.pylori-induced gastric disease. As these proteins are confirmed by functional studies, it may be useful as prognostic indices of H.pylori-related gastric disorders.
目錄

縮寫 1
第一章 導論
第一節 胃癌的發生與幽門螺旋桿菌的關係 3
第二節 幽門螺旋桿菌的流行病學調查 6
第三節 幽門螺旋桿菌如何存活於人體胃部及相關疾病 8
第四節 幽門螺旋桿菌與胃癌的關係及其致癌機轉 11
第五節 總結 17

第二章 實驗材料 19

第三章 實驗方法
第一節 幽門螺旋桿菌感染胃腺癌細胞 22
第二節 幽門螺旋桿菌感染胃腺癌細胞的弁鄔吨尷R 23
第三節 幽門螺旋桿菌urease A蛋白質的選殖、表現與抗體製備 28
第四節 胃腺癌細胞的分離與二維電泳分析 32
第五節 幽門螺旋桿菌感染胃腺癌細胞後有表現量差異的蛋白質鑑定 35

第四章 實驗結果
第一節 幽門螺旋桿菌感染胃腺癌細胞的弁鄔吨尷R 37
第二節 幽門螺旋桿菌ureaseA蛋白質的選殖、表現與抗體製備 38
第三節 胃腺癌細胞的分離與二維電泳分析 39
第四節 幽門螺旋桿菌感染胃腺癌細胞後表現量差異的蛋白質鑑定 39

第五章 討論
第一節 幽門螺旋桿菌感染胃腺癌細胞引發IL-8、iNOS、COX-2增量
表現所代表的生理意義 41
第二節 細胞分離的重要性 42
第三節 有表現量差異的蛋白質其生理上的意義 43
第四節 未來工作及展望 47

第六章 參考文獻 48

第七章 圖表 56

附錄 72
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