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系統識別號 U0026-2907201321521800
論文名稱(中文) 胃癌患者一等親屬的胃癌癌前病變與基因易感性研究
論文名稱(英文) The First-Degree Relatives of Gastric Cancer Patients have Genomic Predisposition to Gastric Cancer Pre-cancer Change
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 蕭微炘
研究生(英文) Wei-Hsin Hsiao
學號 S96001066
學位類別 碩士
語文別 中文
論文頁數 139頁
口試委員 指導教授-許博翔
指導教授-呂政展
召集委員-楊曉白
口試委員-林秋烽
口試委員-鄭修琦
中文關鍵字 胃癌一等親  單核苷酸基因多型性  幽門桿菌  整合素α5β1  Runt-related transcription factor 3  Spasmolytic polypeptide -expressing metaplasia  Trefoil factor 2 
英文關鍵字 First-degree relatives of gastric cancer families  Single nucleotide polymorphisms  Helicobacter pylori  Integrin α5β1  Runt-related transcription factor 3  Spasmolytic polypeptide-expressing metaplasia  Trefoil factor2 
學科別分類
中文摘要 世界衛生組織已經將幽門桿菌感染是胃癌發生的一級致病因子,並且幽門桿菌感染者較容易得到胃癌癌前病變,在過去較廣為人知的如:腸黏膜化生,而有胃癌一等親家屬在過去的研究中也有較高的風險得到胃癌。本研究探討另一新的黏膜化生的癌前病變Spasmolytic polypeptide-expressing metaplasia (SPEM)也是幽門桿菌感染後容易發生的胃癌癌前病變,可能發生在腸黏膜化生之前,並且與Trefoil factor 2 (TFF2)的表現相關,並且當SPEM發生時,壁細胞(parietal cell)會消失伴隨主細胞(chief cell)向上分化轉移。而Runt-related transcription factor 3 (RUNX3)是胃癌的抑癌基因,參與降低癌細胞的生長、分化、增生的調節,在正常的為腺體中,表現在胃上皮細胞,尤其是在主細胞表現。在基因層次的研究中發現,RUNX3啟動子基因活性與胃癌基因易感性增加相關,進一步我們將探討幽門桿菌感染後的胃癌一等親RUNX3與TFF2宿主基因單核苷酸基因多型性與癌前病變SPEM的關連性。而幽門桿菌與整合素(integrin) α5β1的交互作用是重要的傳遞細菌致病因子的方式,並且在過去發現與腸黏膜化生有高度的相關性,但尚未在SPEM有相關研究,因此我們將探討整合素α5β1與SPEM在組織學上的表現關連性與宿主基因單核苷酸基因多型性的關連性。
本研究發現幽門桿菌感染的胃癌一等親比十二指腸潰瘍病人有較高的風險會有SPEM發生,並且胃癌一等親在胃黏膜表層有異常的整合素α5β1表現情形時較容易有advanced SPEM表現。宿主單核苷酸基因多型性分析結果發現胃癌一等親有RUNX3-1714 CC, -1582 CC, -1166 TT, +492 TT單核苷酸基因多型性關連性,而在RUNX3與TFF2單核苷酸基因多型性對SPEM的鑑別力仍有待釐清。胃癌一等親帶有ITGA5-1160 TT和ITGB1-1949 T, -1575 C, +31804 C, +32492 G單核苷酸基因多型性特異性,而整合素α5β1在胃組織上的表現異常與ITGB1-1660 AATTT, -685 G基因同型合子組合有相關性,接著在探討ITGA5與ITGB1啟動子單核苷酸基因多型性差異對啟動子活性的影響能力中,發現在AGS與GES-1胃上皮細胞實驗中,帶有ITGA5-1160 G的ITGA5啟動子活性比ITGA5-1160 T的高,有趣的是在AGS細胞中,幽門桿菌會正向調控ITGA5-1160 T的活性。另一方面,ITGB1啟動子單核苷酸基因多型性差異與幽門桿菌對啟動子區域基因的活性在AGS和GES-1細胞中有不同的調控的能力。
總結本研究的結果:1) 幽門桿菌感染的胃癌一等親有較高的癌前病變SPEM與整合素α5β1異常表現且帶有RUNX3、ITGA5與ITGB1基因單核苷酸多型性特異性;2) 綜合分析後推測在胃癌一等親胃部組織變化可能在幽門桿菌感染後,出現異常的整合素α5β1表現,接著SPEM發生並且進展成advanced SPEM,而腸黏膜化生最後發生;3) ITGA5與ITGB1啟動子單核苷酸基因多型性差異與幽門桿菌能影響啟動子區域基因活性,並且在AGS與GES-1細胞實驗模式中,呈現不同的活性趨勢,此現象有可能會受到轉錄因子所共同調控,而其詳細機制則有待釐清。本研究對臨床醫學研究的貢獻為:1) 對胃癌高風險族群胃癌一等親家屬的癌前病變程度有進一步的了解並提出一可能的變化過程;2) 發現在胃癌一等親中有單核苷酸基因多型性基因易感性以及與整合素α5β1的關連性,可能有助於胃癌癌症預防醫學的進展。
英文摘要 Helicobacter pylori (H. pylori) is a WHO type I carcinogen of gastric cancer with familial clustering predisposing to precancerous change, such as intestinal metaplasia (IM). Spasmolytic polypeptide-expressing metaplasia (SPEM) is a new precancerous lesion, may be earlier than IM after H. pylori infection, and related with trefoil factor2 (TFF2) expression. Previous studies had found that the origin of SPEM is through transdifferentiation from mature chief cell following parietal cell loss. RUNX3, a tumor suppressor, is a member of the runt-domain transcription factor family that regulates the transcription of several genes involved in the decrease of cancer development, differentiation, and proliferation. RUNX3 is expressed in gastric epithelial cells and particularly in chief cell. And the epigenetic change of RUNX3 had found to be associate with gastric cancer. It is interested to validate whether the RUNX3 and TFF2 host genomic predisposition can determine the presence of SPEM after H. pylori infection. H. pylori may interact with integrin α5β1 to translocate virulence factor into cell, and expression of integrin α5β1 is also highly associated with IM. Thereforee, it is wotth investigating the the relationship between integrin α5β1 expression and SPEM development. Furthermore, it should be highly significant to validate if the integrin α5β1 expression and host genomic predisposition correlate with the novel issue SPEM.
In this study, we found the first-degree relatives of gastric cancer families (1st- GCFs) have higher SPEM expression pattern than duodenal ulcer (DU) patients after H. pylori infection, and 1st-GCFs in gastric surface epithelium had abnormal integrin α5β1 expression location, which are closedly associated with advanced SPEM deveopment. 1st-GCFs have host genomic predisposition in RUNX3 single nucleotide polymorphisms (SNP)s at -1714 CC, -1582 CC, -1166 TT, +492 TT. However, the significance of the association between RUNX3 and TFF2 SNPs and SPEM expression level needs furtherer clarification. The 1st- GCFs have higher proportions of ITGA5-1160 TT homozygous and ITGB1-1949 T, -1575 C, +31804 C, +32492 G compared with DU patients. The 1st-GCFs with abnormal integrin α5β1 expression pattern patients have higher proportions of ITGB1-1660 AATTT/AATTT and ITGB1-685 GG homozygous compared with DU patients. Subsequently, we explored whether the different SNPs carrying type could affect the ITGA5 and ITGB1 promoter activity in AGS and GES-1 cell or not. In vitro transfection study in both the AGS and GES-1 cell lines have shown that ITGA5 promoter with -1160 G have higher promoter activity than -1160 T. interestingly, in AGS cells H. pylori can up-regulate the ITGA5 promoter activity with -1160 T. On the other hand, the different ITGB1 promoter SNPs composed and H. pylori infection have dramatic changes in the AGS and GES-1 cells with different regulatory capabilities.
The summarized results of this study: 1) H. pylori-infected 1st-GCFs have higher proportion of precancerous lesion SPEM expression and abnormal integrin α5β1 expression pattern compared with DU patients. Sevral SNPs and haplotype of RUNX3, ITGA5 and ITGB1 are significantly associated with 1st-GCFs compared with DU patients; 2 ) After comprehensive analysis, we speculated that 1st-GCFs stomach tissue changes may occur from abnormal integrin α5β1 expression, followed by SPEM expression and progress to advanced SPEM, and then the IM formed after H. pylori infection; 3) ITGA5 and ITGB1 promoter SNPs may affect promoter activities and H. pylori infection could further influence the promoter activity. Both in AGS or GES-1 cell line experimental modes, the ITGA5 and ITGB1 promoter SNPs may show the different activity trends. These phenomena may be affected by the transcription factors involved; however their detailed mechanisms remain to be clarified. In this study, the contributions of these clinical studies are: 1) to gain more understanding of the gastric cancer high-risk population ie, 1st-GCFs, precancerous lesions pattern and propose a possible change process; 2) The 1st-GCFs have genetic predisposition to the gastric cancer and gastric cancer precancerous changes in integrin α5β1 may provide the diagnostic and therapeutic indices in gastric cancer prevention and management.
論文目次 中文摘要 I
Abstract IV
致謝 VII
目錄 X
表目錄 XIII
圖目錄 XIV
符號及縮寫表 XV
一、緒論 1
1.1前言 1
1.2Spasmolytic polypeptide-expressing metaplasia (SPEM) 5
1.3幽門桿菌與宿主之間的交互作用 10
1.4宿主的角色: RUNX3, TFF2, ITGA5, ITGB1之基因單一核苷酸多型性(Single nucleotide polymorphism, SNP)研究 13
二、研究目的 17
三、材料與方法 19
3.1 臨床研究對象與檢體收集 19
3.2 幽門桿菌感染之檢查 19
3.3 病理指標 20
3.4 人類周邊血液檢體DNA萃取 20
3.5 單一核苷酸多型性(Single nucleotide polymorphism, SNP)的偵測 21
3.6 免疫組織染色法(Immunohistochemistry stain, IHC stain) 24
3.7 免疫組織染色評分方法 26
3.8 構築啟動子報導基因質體 27
3.9 細胞株保存及培養 31
3.10 細胞株總DNA萃取 32
3.11 細胞轉染 32
3.12 幽門桿菌細菌培養及保存 33
3.13 共培養(co-culture)幽門桿菌與胃上皮細胞 34
3.14 螢光酵素酶報導基因分析 34
3.15 總細胞蛋白質萃取 35
3.16 細胞蛋白質濃度測定 35
3.17 西方墨點法 36
3.18 統計方法 37
四、實驗結果 38
4.1研究對象的特性 38
4.2 胃癌一等親Spasmolytic polypeptide-expressing metaplasia (SPEM) 表現較十二指腸潰瘍病人高 38
4.3胃癌一等親RUNX3與TFF2基因多型性 40
4.4胃癌一等親整合素α5β1表現與SPEM之相關性 41
4.5胃癌一等親與十二指腸潰瘍病人整合素α5β1基因ITGA5與ITGB1基因多型性差異探討 42
4.6胃癌一等親整合素α5β1表現位置與ITGB1基因多型性相關 44
4.7In vitro探討整合素α5β1的基因多型性與整合素α5β1基因啟動子之關係與幽門桿菌對其影響之變化 44
4.8探討幽門桿菌在AGS、MKN45、GES-1細胞中對整合素β1總蛋白表現量影響之變化 48
五、討論 49
5.1胃癌一等親比十二指腸潰瘍病人有更高的癌前病變風險 49
5.2RUNX3與TFF2基因多型性特異性 51
5.3整合素α5β1異常表現的胃癌一等親有較高風險得到advanced SPEM病變 54
5.4胃癌一等親有整合素α5β1基因基因多型性特異性 56
5.5整合素β1基因多型性特異性與整合素α5β1 supranuclear clumping 表現相關 57
5.6幽門桿菌與整合素α5β1基因多型性影響整合素α5β1基因啟動子表現量 58
六、結論 62
七、參考文獻 64
八、圖與表 76
九、附錄 118
十、參與的文章發表 138
十一、自述 139
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