前言: 幽門螺旋桿菌(H. pylori)自被發現以來，許多研究報告已確定此細菌能引起胃炎、消化性潰瘍甚至胃癌，且1994年被世界衛生組織列為胃腺癌的第一級致癌物，而國內的研究也認為幽門螺旋桿菌與胃癌有著極大的相關性。最近的研究報告認為幽門螺旋桿菌感染會造成宿主細胞內氧化壓力產生活性氧分子(ROS)，而這些分子的氧化作用會造成上皮細胞増生，細胞凋亡及損傷DNA，並誘發細胞氧氣調控因子HIF-1 α的表現及其轉錄活性。有研究報告指出HIF-1α蛋白之過度表現與許多腫瘤的侵犯、淋巴結轉移、臨床分期、病人存活率及預後都有顯著相關性。組織缺氧亦會經由HIF-1α的表現調控VEGF的大量表現因而促進腫瘤血管生成以及受到腫瘤抑制基因VHL的功能變異影響。而HIF-1a的表現到腫瘤抑制基因VHL的調控，另外ROS誘使Sp1產生氧化作用影響其轉錄功能，尤其在VHL 啟動子的上Sp1 DNA結合位置。我們認為Sp1-pVHL- HIF-1這途徑在幽門螺旋桿菌感染導致胃癌的機制上扮演著一定程度上
的角色。

Introduction: Since the era of Marshall, H. pylori has been to be implicated in many upper digestive tract diseases, such as gastritis, peptic ulcer disease, mucosa- associated lymphoid tissue lymphoma, and even gastric adenocarcinoma. In 1994, WHO recognized H. pylori as a definite carcinogen for gastric cancer. Many study had shown that microbial pathogens may induce oxidative stress in infected host cell. And this may also represent an important mechanism leading to epithelial injury in H. pyloric infection. Oxidative stress plays a role in altering epithelial cell turnover, accelerating apoptosis and increasing oxidative DNA damage. One of the evidences for this phenomenon is increasing level of reactive oxygen species (ROS) measured in the mucosa of infected stomach. ROS may activate HIF-11α transcription. HIF-1α overexpression had been
detected in several human cancers. Furthermore its overexpression
correlates significantly with highly aggressive disease, lymph node
metastasis, clinicopathological status and poor prognosis in some cancer
types. It may up regulate hypoxia-induced gene, such as the vascular
endothelial growth factor (VEGF) transcription and angiogenesis.
Therefore we propose Sp1-pVHL-HIF-1α pathway may play a role the
carcinogenesis in Hp -associated gastric cancer.
Material and methods: We took Paraffin-embedded specimens from 89patients, who had undergone UGI endoscopy and gastric mucosa biopsy.
We assessed the Sp1, pVHL, HIF-1α in all cases by immunohistochemistry
and then evaluated their correlation with the H pylori infection. Chi-square
and Fisher’s exact test was performed to determine the significance of the
difference between Sp1, pVHL, HIF-1α.
Results: There are not significant difference in nuclear Sp1 expression and
H. pylori different (p=0.59). Sp1 expression was not significant, (p=0.91,
0.93, 0.36, 0.42, 0.51) with sex, age, location, TNM stage and cell
differentiation. pVHL protein was mainly expressed in the cytoplasm.
There are no significant difference with H. pylori infection (p=0.14). The
relationship pVHL protein expression between with sex, age, lesion site,
TNM stage and cell differentiation were not significant (p=0.39, 0.70, 0.69,
0.83, 0.70). HIF-1α protein was mainly expressed in the nuclei. There are
not significant association with H. pylori infection (p=0.49). There were
no significant differences between HIF-1α protein expression with sex,
age, location, TNM stage and cell differentiation (p=0.94, 0.32, 0.75, 0.35,
0.60).
Furthermore, In normal tissue the expression of HIF-1α had significant
association with pVHL(p=0.0002), and the expression also had no a
mariginally significant association with Sp1(p=0.096). Expression of Sp1
had significant association with pVHL(p=0.0016)in tumor tissue, Therewas a significant association between normal and tumor tissue expression
of the pVHL and Sp1(p=0.038, 0.019), but the expression of HIF-1α had
no significant(p=0.23).
Conclusion: In this study, we attempt to determine the association
between Sp1-pVHL -HIF-1α pathway and a role in the carcinogenesis in
H. pylori infection. Although we didn’t confirm the hypothesis Sp1-pVHL
-HIF-1α pathway playing an critical role in the mechanism of gastric
cancer. We concluded that there is no significance between the expression
of Sp1, pVHL and HIF-1α and gastric cancer, but the role of this pathway
in the Hp infection associated carcinogenesis is still to be clarified.

中文摘要………...…………………………………………….…………...…i 英文摘要..............………………………………………………….….…….iv
英文縮寫表……..……………………………………………………….…. vii
研究目的…………………………………………………………………….viii
壹、緒論……..………………………………………………………...……..1
一、胃癌之概況.......................................................................................1
二、Sp1 (Specificity protein 1)………..………………….….….……...4
2-1 Sp 基因家族……………………………………………..……4
2-2 Sp家族結構特性………………….…………………….…….4
2-3 Sp1的功能………………………………………………...…..5
2-4 Sp1的生理角色………………………………………….…....7
2-5 Sp1與ROS 之相關性………………………………..….…...8
2-6 Sp1的表現與疾病的關係…………………………………….9
三、von Hippel-Lindau 蛋白質………...………………………....….10
3-1 VHL 基因………………………………………………….…10
3-2 VHL 與 HIF-11α 的關係……………………………….……11
3-3 VHL 與Sp1 的相關性……………………………………….11
3-4 VHL 的表現與疾病的關係…………………………………..12四、缺氧誘導因子(Hypoxic-inducible factor-1, HIF-1)…..……..……13
4-1 HIF-1 基因……………………………………………………13
4-2 HIF-1α 的調節..........................................................................14
4-3 HIF-1α 與ROS 的關係………………………………………15
4-4 HIF-1α 與Sp1 的相關性………………………….…….……174-5 HIF-1α 與疾病的關係..............................................................17
五、幽門螺旋桿菌（Helicobacter pylori）…………….…………..….19
5-1 幽門螺旋桿菌(Hp)……………………………………………19
5-2 Hp 的致病機轉……………………………………………….19
5-3 Hp 的盛行率及與胃腸道疾病的關係………………………..205-4 Hp 與ROS 的相關性………………………………………..21
六、微血管密度(Microvessel density, MVD)........…….………..….….23
貳、材料與方法…………………………………………….……..….……..24
一、設備材料…………………….……………………………..…..…..24
二、檢體收集…………………..……………………………….…..…..25
三、Sp1 免疫組織化學染色及其評估…………………….…..……….26
四、pVHL 免疫組織化學染色及其評估……….………………..……29五、HIF-1α 免疫組織化學染色及其評估……….………….…………32
六、CD34 免疫組織化學染色及其評估 …………………….………..35
七、幽門螺旋桿菌菌株分析……………………………………………38
7-1 幽門螺旋桿菌菌株檢驗分析材料…………………………...38
7-2 幽門螺旋桿菌的培養……………………………………..….39
7-3 幽門螺旋桿菌生化測定……………………………..……….39
八、統計分析………..………………………...…………..……..……..40參、結果…………………………………………………………….……….41
一、病患樣本基本分析………………………………………….……..41
二、Sp1 的表現在幽門螺旋桿感染及胃癌相關性分析………..……..41
三、pVHL 的表現在幽門螺旋桿感染及胃癌相關性分析………...….42
四、HIF-1α 的表現在幽門螺旋桿感染及胃癌相關性分析…….….…43
五、Sp1, pVHL 與HIF-1α在蛋白質表現相關性之分析…….….….…43
六、Sp1, pVHL, HIF-1α與 MVD 在胃癌的相關性探討………..…....44肆、討論……………………………………………………………....….…45
伍、參考文獻…………………………………………………………….…50

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