本實驗分別利用RFLP和自動定序的方式來分析骨髓過氧化酵素基因上游-463的多型性，再利用統計的方式來研究此點多型性與胃癌和十二指腸潰瘍的關係。在表皮細胞黏合素方面則是利用自動定序來分析其基因上游-160的多型性，同樣利用統計來分析此點多型性與廣泛型胃癌的關係。經過性別年齡調整後，胃癌跟十二指腸潰瘍病人的骨髓過氧化酵素基因上游-463的基因型分佈與健康人相比皆無顯著差異(胃癌病人與健康人：p=0.26,

To elucidate the correlation between host susceptible genes and the carcinogenesis of gastric cancer and duodenal ulcer, myeloperoxidase (MPO) -463 G/A polymorphism was detected by PCR-RFLP and nucleotide autosequencing, respectively. On the other hand, E-cadherin (CDH1) -160 C/A polymorphism was analyzed by nucleotide autosequencing. No positive correlation among MPO genotype distributions, gastric cancer (p=0.26,

中文摘要.......................................................................................................i
英文摘要......................................................................................................ii
I. 緒論
1. 胃癌......................................................................................................1
1-1. 飲食習慣與胃癌............................................................................1
1-2. 胃癌組織學.....................................................................................1
1-2-1. 腸型(Intestinal-type)胃癌.......................................................1
1-2-1-1. 表面性胃炎(Superficial gastritis)....................................2
1-2-1-2. 萎縮性胃炎(Atrophic gastritis).......................................2
1-2-1-3. 腸化生(Intestinal metaplasia)..........................................2
1-2-1-4. 分化不良(Dysplasia).......................................................2
1-2-2. 廣泛型(Diffuse-type)胃癌......................................................3
1-2-2-1. 表皮細胞黏合素基因(CDH1)突變.................................3
1-3. 胃癌的預防...................................................................................3
2. 十二指腸潰瘍(Duodenal ulcer)...........................................................3
2-1. 間白素-1 (Interleukin-1)基因家族與免疫反應............................4
2-1-1. 間白素-1基因家族(Interleukin-1 gene family)及其基因多型
性(Polymorphism)..................................................................4
2-2. 十二指腸球狀部(Duodenal bulb)的胃化生(Gastric metaplasia)
以及幽門螺旋桿菌的寄生.............................................................5
3. 幽門螺旋桿菌(Helicobacter pylori, H. pylori)...................................5
3-1. 微生物學(Microbiology)探討幽門螺旋桿菌..............................5
3-1-1. 幽門螺旋桿菌的寄生(Colonization).....................................6
3-1-2. 尿素水解酵素(Urease)...........................................................6
3-2. 病理學(Pathology)探討幽門螺旋桿菌........................................6
3-2-1. 幽門螺旋桿菌吸引發炎細胞(Inflammatory cells)...............7
3-2-2. 幽門螺旋桿菌的致病因子(Virulence factors)及菌株的多樣
性(Strain diversity).................................................................7
4. 骨髓過氧化酵素(Myeloperoxidase, MPO).........................................8
4-1. 骨髓過氧化酵素與其功能(function)...........................................8
4-2. 骨髓過氧化酵素處理過程(Processing)........................................8
4-3. 次氯酸(HOCl)的製造...................................................................9
4-4. 骨髓過氧化酵素基因上游-463基因多型性(Polymorphism)......9
4-5. 骨髓過氧化酵素與幽門螺旋桿菌..............................................10
5. 表皮細胞黏合素(E-cadherin ,CDH1)................................................10
5-1. 表皮細胞黏著素與其功能..........................................................10
5-2. 細胞與細胞間黏著結構(Cell-cell adhesion complex)...............10
5-3. 表皮細胞黏著素功能的不正常或喪失與癌症的發生的關係
(carcinogenesis)..........................................................................11
5-4. 表皮細胞黏合素基因(CDH1)上游-160基因多型性................11
II. 實驗目的...............................................................................................12
III. 材料與方法..........................................................................................13
1.藥品與儀器...........................................................................................13
2.DNA樣本的蒐集.................................................................................14
3.DNA 萃取............................................................................................14
4.基因型分析...........................................................................................15
5.統計分析...............................................................................................15
IV. 結果......................................................................................................16
1. 胃癌病人MPO-463基因型分析.......................................................16
1-1. MPO -463基因型分析中樣本的基本資料.................................16
1-2. 胃癌病人MPO -463基因型分析.................................................16
1-3. 胃癌病人MPO -463對偶基因頻率(allele frequencies)分析......16
1-4. 幽門螺旋桿菌感染的樣本之MPO -463基因型分析.................17
1-5. 腸型胃癌病人MPO -463基因型的分析.....................................17
1-6. 廣泛型胃癌病人MPO -463基因型的分析.................................17
1-7. 吸煙習慣的樣本之MPO -463基因型的分析.............................18
1-8. 喝酒習慣的樣本之MPO -463基因型分析.................................18
2. 廣泛型胃癌病人CDH1-160基因型分析.........................................18
2-1. CDH1 -160基因型分析中樣本的基本資料................................18
2-2. 廣泛型胃癌病人CDH1 -160基因型分析...................................19
2.3. 廣泛型胃癌病人CDH1-160對偶基因頻率分析........................19
2-4. 幽門螺旋桿菌感染的樣本之CDH1 -160基因型分析...............19
2-5. 吸煙習慣的樣本之CDH1 -160基因型分析...............................20
2-6. 喝酒習慣的樣本之CDH1 -160基因型分析...............................20
2-7. 發生腫瘤轉移的廣泛型胃癌病人CDH1 -160基因型的分析..20
2-8. 廣泛型胃癌病人與健康人的血型分析......................................20
3. 十二指腸潰瘍病人MPO-463基因型分析..........................................21
3-1. MPO -463基因型分析中樣本的基本資料.................................21
3-2. 十二指腸潰瘍病人MPO -463基因型分析.................................21
3-3. 十二指腸潰瘍病人MPO -463對偶基因頻率分析.....................22
3-4. 幽門螺旋桿菌感染的樣本之MPO -463基因型分析.................22
3-5. 吸煙習慣的樣本之MPO -463基因型分析.................................22
3-6. 喝酒習慣的樣本之MPO -463基因型分析.................................23
V. 討論...........................................................................................................24
1. 胃癌病人MPO -463基因型分佈與胃癌以及胃癌危險因子的相關
性........................................................................................................24
2. 廣泛型胃癌病人CDH1-160基因型分佈與胃癌以及胃癌危險因子
的相關性............................................................................................25
3. 十二指腸潰瘍病人MPO-463基因型分佈與潰瘍以及潰瘍危險因
子的相關性........................................................................................26
VI. 參考文獻..............................................................................................27
表目錄
表1. 分析MPO -463G/A的引子、PCR條件以及限制酵素作用條件..34
表2 分析CDH1 -160C/A的引子及PCR條件.......................................35
表3. 胃癌MPO基因型分析中樣本資料................................................36
表4. MPO -463 基因型頻率對胃癌危險比率之影響及p值.................37
表5. MPO -463 對偶基因頻率對胃癌危險比率之影響及p值…….....38
表6. 受幽門螺旋桿菌感染的MPO -463基因型頻率對胃癌危險比率之
影響及p值......................................................................................39
表7. 未受幽門螺旋桿菌感染的MPO -463基因型頻率對胃癌危險比率之影響及p值..................................................................................40
表8. MPO -463基因型頻率對腸型胃癌危險比率之影響及p值...........41
表9. MPO -463基因型頻率對廣泛型胃癌危險比率之影響及p值…...42
表10. 有吸煙習慣的MPO -463基因型頻率對胃癌危險比率之影響及p值..................................................................................................43
表11. 有喝酒習慣的MPO -463基因型頻率對胃癌危險比率之影響及p值.............................................................................................. 44
表12. CDH1基因型分析中樣本資料....................................................45
表13. CDH1 -160 基因型頻率對廣泛型胃癌危險比率之影響及p值
......................................................................................................46
表14. CDH1 -160 對偶基因頻率對廣泛型胃癌危險比率之影響及p值..................................................................................................47
表15. 受幽門螺旋桿菌感染的CDH1 -160基因型頻率對廣泛型胃癌危險比率之影響及p值….........................................................48
表16. 未受幽門螺旋桿菌感染的CDH1 -160基因型頻率對廣泛型胃癌危險比率之影響及p值.........................................................49
表17. 有吸煙習慣的CDH1 -160基因型頻率對廣泛型胃癌危險比率之影響及p值..............................................................................50
表18. 有喝酒習慣的CDH1 -160基因型頻率對廣泛型胃癌危險比率之影響及p值…….......................................................................51
表19. CDH1 -160基因型頻率對廣泛型胃癌發生轉移危險比率之影響及p值...........................................................................................52
表20. 血型對廣泛型胃癌危險比率之影響及p值..............................53
表21. 十二指腸潰瘍MPO基因型分析中樣本資料............................54
表22. MPO -463 基因型頻率對十二指腸潰瘍危險比率之影響以及p值..................................................................................................55
表23. MPO -463 對偶基因頻率對十二指腸潰瘍危險比率之影響以及p值...............................................................................................56
表24. 受幽門螺旋桿菌感染的MPO -463 基因型頻率對十二指腸潰
瘍危險比率之影響以及p值.......................................................57
表25. 未受幽門螺旋桿菌感染的MPO -463 基因型頻率對十二指腸潰瘍危險比率之影響及p值.......... ............................................58
表26. 有抽煙習慣的樣本之MPO -463 基因型頻率對十二指腸潰
瘍危險比率之影響及p值..........................................................59
表27. 有喝酒習慣的MPO -463 基因型頻率對十二指腸潰瘍危險比率之影響以及p值......................................................................60
表28. 在螢光顯微鏡下不同幽門螺旋桿菌濃度造成細胞凋亡的比
率..................................................................................................94
表29. 在細胞計數器下不同幽門螺旋桿菌濃度造成的細胞死亡率(懸浮細胞)........................................................................................95
表30. 在細胞計數器下不同幽門螺旋桿菌濃度造成的細胞死亡率
(懸浮細胞+附著細胞)...............................................................96
圖目錄
圖1. 幽門螺旋桿菌寄生在胃部的示意圖............................................61
圖2. 表皮細胞黏合素示意圖.................................................................62
圖3. 細胞間表皮細胞黏著素作用示意圖.............................................62
圖4. 細胞間黏著力喪失造成良性腫瘤轉形成惡性腫瘤.....................63
圖5. MPO -463基因型分析RFLP電泳圖...............................................64
圖6. CDH1-160基因型分析結果..........................................................65
圖7. 帶有RFP的SUMOs在AGS細胞株內的表現及位置..............87
圖8. 帶有RFP的SUMOs在293細胞株內的表現及位置................87
圖9. 在螢光顯微鏡下凋亡細胞的細胞核外觀....................................90
圖10. 在螢光顯微鏡下不同幽門螺旋桿菌濃度造成細胞凋亡的比率
長條圖..........................................................................................94
圖11. 在細胞計數器下不同幽門螺旋桿菌濃度造成的細胞死亡率長
條圖(懸浮細胞)...........................................................................95
圖12. 在細胞計數器下不同幽門螺旋桿菌濃度造成的細胞死亡率長
條圖 (懸浮細胞+附著細胞).......................................................96
圖13. 對於各細胞株做PCR偵測SUMO-1, SUMO-2, Daxx1, Daxx4
以及Daxx的電泳結果..............................................................100附錄
附錄註解..................................................................................................66
附錄1. MPO基因型分析中胃癌病人資料............................................67
附錄2. MPO基因型分析中健康人資料................................................72
附錄3. CDH1基因型分析中廣泛型胃癌病人與健康人資料..............78
附錄4. MPO基因型分析中十二指腸潰瘍病人資料............................80
附錄5. SUMO在293和AGS細胞株裡的表現(expression)和位置
(localization)................................................................................84
附錄6. 評估幽門螺旋桿菌對於AGS細胞株造成的凋亡(apoptosis).89
附錄7. 利用PCR偵測六種胃癌細胞株內是否具有SUMO-1、
SUMO-2、Daxx1、Daxx2以及Daxx全長的基因.....................97
附錄8. 其他統計數據………………………………………………..101

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