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系統識別號 U0026-0812200915303180
論文名稱(中文) 細菌和宿主因子與幽門桿菌相關之胃黏膜腸化生的關係
論文名稱(英文) The bacterial and host factors related to the Helicobacter pylori-associated gastric intestinal metaplasia
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 97
學期 2
出版年 98
研究生(中文) 洪貴香
研究生(英文) Kuei-Hsiang Hung
電子信箱 s5892151@ccmail.ncku.edu.tw
學號 s5892151
學位類別 博士
語文別 中文
論文頁數 121頁
口試委員 指導教授-許博翔
指導教授-吳俊忠
口試委員-吳明賢
召集委員-呂政展
口試委員-黎煥耀
口試委員-許博欽
中文關鍵字 胃黏膜腸化生  環氧化酶-2  Wnt/β-catenin路徑  幽門桿菌 
英文關鍵字 Helicobacter pylori  gastric intestinal metaplasia  Wnt/β-catenin pathway  cyclooxygenase-2 
學科別分類
中文摘要 幽門桿菌感染與宿主因子是造成胃黏膜癌前病變,如胃黏膜萎縮和胃黏膜腸化生的重要因素。幽門桿菌感染會促使胃黏膜細胞分泌環氧化酶-2 (cyclooxygenase-2; COX-2),以幫助細胞增生、維持組織架構。幽門桿菌亦會活化Wnt/β-catenin路徑,使β-catenin進入細胞核中調節包括COX-2等分子的表達。已知COX-2和β-catenin會大量表現於胃癌前病變和胃癌組織上。γ-glutamyltranspeptidase (GGT) 和cytotoxin-associated gene-A (CagA) 是調節COX-2和β-catenin的重要幽門桿菌因子。本論文的第一部分旨在探討幽門桿菌因子與胃黏膜癌前病變的關係。CagA會調控β-catenin,使原本與E-cadherin和actin形成複合物的β-catenin自細胞膜上脫離。幽門桿菌會讓細胞質中的GSK3β被磷酸化,使β-catenin可進入細胞核中;此GSK3β被磷酸化的現象不受CagA、GGT或VacA(Vacuolating cytotoxin A)調控。VacA i region cluster B的第九個氨基酸若為甘氨酸,則宿主發生胃黏膜腸化生的機會高達9.8倍(P = 0.017;95% CI 1.50-63.85)。GGT除了可調控COX-2外,還能刺激IL-1β、IL-8和TNFα表現。本論文的第二部分旨在探討宿主因子與胃黏膜癌前病變的關係。幽門桿菌感染合併有胃黏膜腸化生的患者,其除菌前細胞核內β-catenin愈多,則除菌後胃黏膜腸化生愈不容易消失。若其大腸瘜肉症蛋白基因(adenomatous polyposis coli protein; APC)在核苷酸4479、5268和5465分別為AGA/AGA,加上細胞核內大量表達β-catenin,則除菌後胃黏膜腸化生不消的比例高達4.5倍(P = 0.045;95% CI 1.33-15.28)。本論文的第三部分旨在探討幽門桿菌根除治療以及使用選擇性COX-2抑制劑celecoxib,改善胃黏膜癌前病變的效果。根除幽門桿菌不僅能有效降低發炎、COX-2和細胞核內β-catenin表現,還可使32.3%患者的胃黏膜腸化生消失。每日口服200毫克celecoxib持續八週可降低發炎情況,並且讓28.6%患者的胃黏膜腸化生消失;若延長至二十週又能再讓33.3%患者的胃黏膜腸化生消失。然而,口服celecoxib八週並沒有明顯抑制COX-2和細胞核內β-catenin表現的效果。總結本論文的研究,Wnt/β-catenin路徑是決定除菌後胃黏膜腸化生消失與否的重要關鍵。幽門桿菌根除治療以及使用選擇性COX-2抑制劑celecoxib皆有助於改善胃黏膜癌前病變。
英文摘要 Gastric precancerous changes, such as atrophy and intestinal metaplasia (IM), are caused by Helicobacter pylori infection and different host genetic background. Cyclooxygenase-2 (COX-2) is secreted from gastric mucosa to activate cell proliferation and maintain tissue structure when host is infected with H. pylori. Wnt/β-catenin pathway is also activated by H. pylori and leads β-catenin entry to the nucleus to regulate many molecules expressions, including COX-2. Overexpression of COX-2 and β-catenin could be commonly disclosed on the gastric tissues with in premalignant and malignant changes. Helicobacter pylori γ-glutamyltranspeptidase (GGT) and cytotoxin-associated gene-A (CagA) are bacterial factors which can regulate the COX-2 and β-catenin expressions, respectively. The first part of the thesis aimed to investigate the relationship between H. pylori factors and gastric precancerous changes. Helicobacter pylori CagA interacts with E-cadherin/β-catenin/actin complex and disassociate the β-catenin on the cell membrane. Helicobacter pylori, irrespective of their CagA, GGT, or VacA (Vacuolating cytotoxin A) status, can enhance a higher GSK-3β phosphorylation. We at first disclosed the substitution of a G for the third S in the i1-type cluster B sequence of VacA conferred a greater risk of gastric IM up to 9.8 (P = 0.017). In addition to the up-regulation of COX-2, GGT also has the ability to stimulate the expressions of IL-1β, IL-8, and TNFα. The second part of the thesis aimed to investigate the relationship between host factors and gastric precancerous changes. There were a significantly increased number of patients with high-level β-catenin nuclear staining in patients with IM persistence compared with those without IM persistence after H. pylori eradication. When the two factors of host AGA genotype APC SNP and high-level nuclear β-catenin expression were combined, these patients had an increased relative risk of up to 4.5 (P = 0.045) of IM persistence compared with hosts with the non-AGA genotype and low-level nuclear β-catenin expression. The third part of the thesis aimed to investigate the effect of H. pylori eradication and using selective COX-2 inhibitor celecoxib on improving gastric precancerous lesions. Clearance of H. pylori leads to downregulation of inflammation, COX-2, and nuclear β-catenin translocation, and improving 32.3% of patients with regression of IM. Eight weeks celecoxib treatment with 200 mg celecoxib once daily not only decreasing the inflammation but also improving 28.6% of patients with regression of IM; prolong celecoxib treatment to 20 weeks, the regression rate of IM was 33.3%. However, there was no significantly decrease the expression of COX-2 and nuclear β-catenin translocation during celecoxib treatment. In conclusion, host Wnt/β-catenin pathway triggered by H. pylori correlates with regression of gastric IM after H. pylori eradication. Clearance of H. pylori infection and using selective COX-2 inhibitor celecoxib should be helpful to improve residual IM.
論文目次 中文摘要……………………………………………………………….. I
英文摘要……………………………………………………………….. III
誌謝…………………………………………………………………….. V
目錄…………………………………………………………………….. VI
表目錄………………………………………………………………….. VIII
圖目錄………………………………………………………………….. IX
符號與縮寫…………………………………………………………….. XI
緒論…………………………………………………………………….. 1
一、幽門桿菌的發現……………………………………………… 1
二、幽門桿菌的分類與特性……………………………………… 1
三、幽門桿菌的感染率…………………………………………… 3
四、幽門桿菌的治療與抗藥性現況……………………………… 3
五、參與胃癌化過程的幽門桿菌毒力因子……………………… 4
六、胃癌化過程的演進…………………………………………… 8
七、胃黏膜腸化生………………………………………………… 9
八、環氧化酶-2與胃癌化過程…………………………………… 10
研究動機與實驗設計.............................................................................. 13
材料與方法…………………………………………………………….. 15
結果…………………………………………………………………….. 32
一、幽門桿菌因子與胃癌前病變的關係………………………… 32
1.1 CagA…………………………………………………….. 32
1.2 vacA基因多型性和VacA造成宿主細胞空泡化的差異... 33
1.3 GGT酵素活性的差異…………………………………... 34
二、宿主因子與胃癌前病變的關係……………………………… 34
2.1 COX-2…………………………………………………… 34
2.2 Wnt/β-catenin……………………………………………. 35
2.3 構築ggt突變株………………………………………….. 36
2.4 幽門桿菌CagA調控Wnt/β-catenin路徑………………... 38
2.5 幽門桿菌GGT調節發炎細胞激素…………………….. 38
2.6 構築ggt互補株及GGT表達質體………………………. 39
三、幽門桿菌根除治療以及使用選擇性COX-2抑制劑
「celecoxib」,改善胃黏膜癌前病變的效果………………. 40
3.1 幽門桿菌根除治療並且長期追蹤有助於改善胃黏膜
腸化生………………………………………………….......... 40
3.2 Celecoxib治療能有效改善胃黏膜腸化生…………….... 41
3.3 Celecoxib改善胃黏膜腸化生的機轉………………….... 43
討論…………………………………………………………………….. 45
結論與未來展望……………………………………………………….. 59
參考文獻……………………………………………………………….. 61
圖表…………………………………………………………………….. 73
附錄…………………………………………………………………….. 105
著作發表和獎項……………………………………………………….. 119
自述…………………………………………………………………….. 121
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