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系統識別號 U0026-0205201218185500
論文名稱(中文) 幽門桿菌 CagL, CagI 及基質金屬蛋白酵素多型性於胃癌致病機制之角色
論文名稱(英文) Roles of Helicobacter pylori CagL, CagI and Matrix Metalloproteinases Polymorphisms in Gastric Carcinogenesis
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 100
學期 2
出版年 101
研究生(中文) 葉怡君
研究生(英文) Yi-Chun Yeh
電子信箱 yyc0110@yahoo.com.tw
學號 s58931439
學位類別 博士
語文別 英文
論文頁數 146頁
口試委員 指導教授-許博翔
召集委員-吳俊忠
口試委員-許博欽
口試委員-楊曉白
口試委員-呂政展
口試委員-莊偉哲
中文關鍵字 幽門桿菌  CagL  CagI  基質金屬蛋白酵素  胃癌 
英文關鍵字 Helicobacter pylori  CagL  CagI  Matrix Metalloproteinases  Gastric cancer 
學科別分類
中文摘要 幽門桿菌的感染造成胃黏膜急性或慢性發炎,與胃潰瘍、十二指腸潰瘍與胃癌的形成有著密切的關連。在西方國家,幽門桿菌cagA與vacA等毒力因子跟疾病的產生有極大的關連性,尤其是CagA透過cag致病島(cag Pathogenic Island, cag-PAI)所encode的第四型分泌系統(Type IV secretary system, T4SS),將CagA注入宿主細胞中,與胃癌發生最具關聯。然而台灣的幽門桿菌株cagA與vacA基因陽性率幾乎達100%,因此與臨床疾病表現無關。
Integrin α5β1在幽門桿菌傳送CagA過程中作為受體的角色。此外,幽門桿菌組成第四型分泌系統組成之ㄧCagL,能與integrin 作特異性結合,CagL與integrin的結合除了扮演傳送CagA之外,還進一步活化integrin下游參與CagA磷酸化之激酶。為了探討究竟CagL是否在致病上扮演角色,特別是在cagA-vagA-babA2為陽性的台灣臨床菌株,我們分析幽門桿菌臨床菌株發現cagL基因陽性率近乎100%,經由定序分析幾乎都帶有RGD序列。進一步分析胺基酸序列之多型性與床診斷之關係發現,CagL-Y58/E59序列與高胃癌風險相關,其風險達4.6倍,並且與增加胃體部的integrin α5β1表現有關,而此表現也反映出胃體部有較厲害的發炎反應。在體外細胞實驗發現,在CagL-Y58/E59之幽門桿菌感染下,使AGS胃上皮細胞株有較多的integrin β1活化狀態,表示integrin clustering的程度較高,及有較多的CagA蛋白被磷酸化,顯示傳遞CagA蛋白進入宿主細胞的能力較強,也促進胃上皮細胞株分泌較多的IL-8,及較高比例細胞發生細胞凋亡。由於降低胃酸分泌與胃癌的發生有關,我們觀察在較高的pH值的環境之下,CagA蛋白被磷酸化的程度較高,此外也使integrin的表現增加。
除了CagL將integrin α5β1作為受體,CagI與CagY同樣會與integrin α5β1結合,因此我們這兩者的盛行率或序列多行性是否與疾病相關。分析結果cagI與cagY基因的陽性率同樣幾近100%。進一步分析其胺基酸序列發現,CagI-N125也顯著與胃癌相關,比起非CagI-N125幽門桿菌感染其致胃癌風險為4.5倍。CagI-N125幽門桿菌感染同樣使AGS胃上皮細胞株有較多的integrin β1活化狀態,但在傳遞CagA蛋白的能力則無差異。至於CagY系列多行性則與胃癌無關,但與胃潰瘍有關。感染CagY-I1725之幽門桿菌,其致胃潰瘍的風險為3.7倍。
Matrix metalloproteinases (MMPs) 是一群能分解大多數細胞外基質的蛋白酶,在正常情況下參與組織修復、生長、發育與修補等過程。然而,若MMP表現及活性調節失去平衡,則可能導致疾病發生。近年來有研究指出,MMP與多種發炎性與癌症發展有密切關聯。而幽門桿菌的感染,亦會誘發組織細胞釋放多種的MMPs。因此我們探討幽門桿菌感染的患者,其MMPs的血清濃度以及基因多行性是否與疾病相關。我們發現幽門桿菌感染之胃癌患者,其血清中MMP-3及MMP-7濃度高於十二指腸與胃炎患者。胃癌患者同時表現較高的MMP-3與MMP-7在血清中,則會有較低的存活率。在MMPs及其抑制蛋白TIMPs的基因多行性分析,我們發現女性十二指腸潰瘍患者有較高比例帶有MMP-3 -1612基因型為6A6A。當合併MMP-3/TIMP-1基因型為6A6A/CC時,罹患十二指腸的風險提升至3.6倍。台灣女性在感染幽門桿菌感染後導致十二指腸潰瘍發生,可能與MMP-3啟動子的基因多行有關。
英文摘要 Helicobacter pylori infection has been well-recognized to closely associate with a spectrum of pathologies, ranging from mild gastritis to peptic ulcer and even gastric malignancy in humans. The cagA and vacA are the two major virulence factors of H. pylori that have been associated with disease induction. However, in Taiwan, the cagA-genopositive or vacA genopositive H. pylori infection was nearly to 100% and thus showed poor correlation to explain the different outcomes.
Integrin α5β1 has been well recognized as a receptor for the delivery of CagA protein. Moreover, the CagL protein of H. pylori is an integrin-specific adhesion, and the CagL-integrin interaction by itself activates an integrin-associated kinase cascade for CagA phosphorylation. We tested whether cagL genopositivity or amino acid sequence polymorphisms of H. pylori correlated with the more adverse clinical-pathological outcomes, such as gastric cancer, and whether CagL interact with host gastric integrin α5β1 expressions, and correlate with the clinicohistological outcomes. We found that nearly 100% of the H. pylori isolates had cagL-positive genotype and with RGD motif. H. pylori CagL amino acid polymorphisms as Y58/E59 has a 4.6-fold risk of gastric cancers, and exerted with a corpus shift-up of gastric integrin α5β1 to mediate more severe corpus gastritis. The gastric epithelial cell AGS infected with CagL-Y58/E59 H. pylori had higher integrin β1 activation and clustering, more CagA phosphorylation to have more CagA translocation into cells, higher IL-8 secretion, and apoptosis rate. As low acid secretion happen in gastric cancer patients to correlate with gastric cancer progression. We therefore tested whether pH condition affect CagA phosphorylation or integrin expression, and found that higher level of CagA phosphorylation and integrin expression were mediated by H. pylori in higher pH condition.
Besides to CagL, CagI and CagY also interact with integrin α5β1. We examined whether cagI and cagY genopositive or amino acid sequence polymorphisms of H. pylori correlated with clinical outcomes. We found the prevalence rates of cagI and cagY are nearly 100%. H. pylori CagI amino acid polymorphism as N125 correlates with a 4.5-fold risk of gastric cancers. In in vitro study, the AGS infected with CagI-N125 H. pylori could exert with higher integrin β1 activation, rather than affect the ability of CagA translocation into cells. H. pylori CagY amino acid polymorphisms have no correlation to gastric cancers, but H. pylori CagY-I1725 infection correlates with a 3.7-fold risk of gastric ulcers.
Matrix metalloproteinases (MMPs) are a family of enzymes that degrade most extracellular matrix and participate in the processes of tissue repairing, growth, development and remodeling. However, when the expressions and activities of MMPs lose control, MMPs may be associated with some diseases. Recent studied indicated that MMPs play important roles in many inflammatory diseases processes, and some studies reported that several MMPs can be induced during H. pylori infection. We therefore examined whether the serum levels or single nucleotide polymorphisms (SNPs) of MMPs may correlate with the clinical outcomes. Among the H. pylori-infected subjects, the gastric cancer patients had higher serum levels of MMP-3 and MMP-7 than those with duodenal ulcer and gastritis. Moreover, the concomitant elevations of MMP-3 and MMP-7 serum levels in the H. pylori-infected gastric cancer patients correlate to a poor survival. Our SNP analysis revealed that the MMP-3 6A6A genotype were more common in the patients with duodenal ulcers than in those with gastritis in H. pylori-infected females. Combining the MMP-3/TIMP-1 genotypes as 6A6A/CC, the risk of duodenal ulcer may increase up to 3.6 folds in the H. pylori-infected females. So the MMP-3 promoter polymorphism may correlate to duodenal ulcer formation after H. pylori infection in the Taiwanese females.
論文目次 中文摘要 III
Abstract V
致謝 VII
Table of contents VIII
Table list XIV
Figure list XVI
Abbreviations XIX
Chapter 1 Introduction 1
1.1 Bacteria factors 2
1.1.1 Colonization 2
1.1.1.1 Urease 2
1.1.1.2 Flagella 3
1.1.1.3 Adhesin 4
1.1.1.3(1) Blood group antigens binding adhesion (BabA) 4
1.1.1.3(2) Sialic acid–binding adhesion (SabA) 4
1.1.2 Virulence factors 6
1.1.2.1 cag pathogenicity island (cag-PAI) 6
1.1.2.2 CagA and carcinogenesis 6
1.1.2.3 CagL 8
1.1.2.4 CagI 9
1.1.2.5 CagY 10
1.1.3 The vacuolating cytotoxin (VacA) 11
1.1.4 Duodenal ulcer-promoting gene A (dupA) 12
1.2 Host factors 12
1.2.1 Integrin 12
1.2.2 Decreased acid secretion and development of gastric cancer 13
1.2.3 Matrix metalloproteinases (MMPs) 14
1.2.4 Tissue inhibitors of metalloproteinases (TIMPs) 16
1.2.5 Single nucleotide polymorphisms (SNPs) of MMPs and TIMPs and gastroduodenal ulcer 17
Chapter 2 Objective and specific aims 18
Chapter 3 Materials and methods 19
3.1 Patients and study design 19
3.1.1 Study of H. pylori CagL, CagI, and CagY polymorphisms and its biological functions in gastric carcinogenesis 19
3.1.1(1) H. pylori-related histology 20
3.1.1(2) Immunochemical staining for the expression of gastric integrin α5β1 20
3.1.2 Study of serum levels of MMPs as biomarker of gastric cancers 21
3.1.2(1) Clinicopathologic features and survival of gastric cancer Patients 22
3.1.3 The prevalence of dupA and SNPs of MMPs/TIMPs in gastroduodenal ulcers 22
3.2 Bacterial strains, plasmids, and culture conditions 23
3.3 Cell lines and cell culture conditions 24
3.4 Growth curve of H. pylori 1033 wild type, cagL mutant, cagI mutant, and amino acid replacement mutants 24
3.5 DNA manipulation 25
3.5.1 Plasmid DNA extraction 25
3.5.2 H. pylori Genomic DNA extraction 25
3.5.3 Human genomic DNA extraction 26
3.5.4 PCR for detection of dupA, cagL, cagI, and cagY genotypes 27
3.5.5 cagI, cagL and cagY-genosequencing for translating into amino acid sequences 27
3.5.6 Restriction enzyme digestion 27
3.5.7 Extract DNA from agarose gel 28
3.5.8 DNA ligation 28
3.5.9 Site-directed mutagenesis 28
3.5.10 E. coli competent cell preparation 29
3.5.11 Heat-shock transformation 30
3.5.12 Natural transformation of H. pylori 30
3.5.13 Sequencing 30
3.5.14 Construction of the cagL insertion mutant 31
3.5.15 Construction of CagL amino acid replacement mutants 31
3.5.16 Construction of the cagI insertion mutant 32
3.5.17 Construction of CagI amino acid replacement mutants 32
3.5.18 Genotypes of SNPs in MMPs and TIMPs 33
3.6 RNA manipulation 33
3.6.1 RNA extraction 33
3.6.2 Reverse transcription 34
3.6.3 Real-time PCR analysis 34
3.7 Protein manipulation 35
3.7.1 Preparation of cell lysate 35
3.7.2 Protein concentration measurement 35
3.7.3 Western blot analysis 36
3.8 Cell manipulation 36
3.8.1 Infection of AGS cells with H. pylori 36
3.8.2 IL-8 level culture supernatant was measured with ELISA 37
3.8.3 Cell cycle was analyzed by using flow cytometry 37
3.8.4 Serum levels of MMP-3, -7, and -9 were measured with ELISA 37
3.9 Statistical Analysis 38
3.9.1 Study of polymorphisms of cagL, cagI, and cagY, and integrin expression 38
3.9.2 Study of serum levels of MMPs of gastrointestinal diseases patients 39
3.9.3 Study of SNPs of MMPs and TIMPs 39
Chapter 4 Results 40
4.1 Study of H. pylori CagL, CagI, and CagY polymorphisms and its biological functions in gastric carcinogenesis 40
4.1.1 Demographic characteristics of the study groups 40
4.1.2 The prevalence of cagL genotype of H. pylori infection 40
4.1.3 The CagL-amino acid sequence polymorphisms and clinical disease outcomes 41
4.1.4 Antral predominant expression of gastric integrin α5β1 in human subjects 41
4.1.5 H. pylori loads, inflammation, and IM irrespective of integrin α5β1 intensity 42
4.1.6 H. pylori CagL-Y58/E59 with corpus shift-up of integrin α5β1 in non-cancer patients 42
4.1.7 Combined impact of CagL-Y58/E59 and corpus shift-up of integrin on histopathology 43
4.1.8 Lower or Even the Absence of Integrin α5β1 in Cancer Tissue Versus Non-cancer Tissue 43
4.1.9 Growth curves of the H. pylori cagL isogenic mutant, cagL revertant, and amino acid replacement mutants 44
4.1.10 H. pylori with CagL as Y58/E59 can induce higher activation of integrin β1 than others 44
4.1.11 Higher CagA translocation in H. pylori with CagL as Y58/E59 45
4.1.12 Effect of CagL as Y58/E59 on IL-8 secretion in gastric epithelial cells 46
4.1.13 CagL as Y58/E59 on cell cycle regulation in gastric epithelial cells 46
4.1.14 Integrin upregulation by H. pylori with CagL-Y58/E59 polymorphisms 47
4.1.15 Integrin α5 up-regulation by H. pylori is pH dependent manner rather than integrin β1 47
4.1.16 Degree of CagA phosphorylation is as well pH-dependent in manner 48
4.1.17 The prevalence of cagI and cagY genotype of H. pylori infection 48
4.1.18 The CagI-amino acid sequence polymorphisms and clinical outcomes 49
4.1.19 The CagY-amino acid sequence polymorphisms and clinical outcomes 49
4.1.20 H. pylori CagI-N125 did not reveal corpus shift-up of integrin α5β1 in non-cancer patients 50
4.1.21 The growth curves of Hp1033 cagI isogenic mutant, cagI revertant, and the amino acid replacement mutants 50
4.1.22 H. pylori with CagI as N125 induce higher integrin β1 than N125K at acidic pH level 50
4.1.23 H. pylori with CagI as N125 has a trend of higher CagA translocation 51
4.2 The serum MMP-3, -7, and -9 Levels of the different clinical diseases 52
4.2.1 The serum MMP-3, -7, and -9 Levels of the different clinical diseases 52
4.2.2 The predictive performance of serum MMP-3, -7, and -9 levels to gastric cancer after H. pylori infection 52
4.2.3 Factors related to an elevated MMP-3 or -7 in gastric cancer patients 53
4.2.4 Associations between MMP-3 or -7 Levels and gastric cancer survival 53
4.3 H. pylori dupA and Host SNPs of MMPs/TIMPs in gastroduodenal ulcers 55
4.3.1 Demographic features of the study subjects 55
4.3.2 Prevalence of dupA H. pylori infection in patients 55
4.3.3 The MMP/TIMP genotypes and the H. pylori-related peptic ulcers 55
Chapter 5 Discussion and conclusions 57
5.1 H. pylori CagL, CagI, and CagY polymorphisms and its biological functions in gastric carcinogenesis 57
5.2 Serum levels of MMPs as biomarker of gastric cancers and polymorphisms of MMPs in gastroduodenal ulcers 63
5.3 Matrix metalloproteinase SNPs 67
References 70
Tables 86
Figures 106
Appendix 136
1: Chemicals and reagents 136
2: Media and solutions 140
Publications 145
自述 146

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