胃癌是世界癌症死亡原因之一，其中又好發於東亞和東南亞，包括台灣。胃癌的致病機轉，一般認為是經由多重因素及步驟所導致的；許多研究已證實，幽門螺旋桿菌是導致胃癌發生的的一個危險因子，受感染的人類胃上皮細胞，會形成胃發炎、胃潰瘍、最終導致胃癌。然而，幽門螺旋桿菌誘導胃癌的致病機制目前還不是很清楚，尤其是當胃部細胞受幽門螺旋桿菌感染後，其與細胞內的某些生長因子相互影響，進而導致胃癌的機制更是無法釐清。肝癌衍生生長因子(hepatoma-derived growth factor；HDGF) 是近期發現的一種新型生長因子，它在許多癌症之致病過程中都扮演很重要的角色。過去研究也指出，其過度表現會促使胃癌細胞之增生及轉移，並造成不良之預後。此外， HDGF 會藉由調控上皮-間質轉化 (epithelial mesenchymal transition；EMT），使腫瘤細胞進行轉移。本研究，利用胃上皮 AGS 細胞感染幽門螺旋桿菌之模式，探討 HDGF 與幽門螺旋桿菌導致胃癌間的關係，藉此了解更多胃癌發生之可能機轉。結果發現，以幽門螺旋桿菌 (ATCC49503) 感染之 AGS 細胞比未被幽門螺旋桿菌感染的 AGS 細胞，有較高的 HDGF 表現及釋放。在免疫組織化學染色方面，統計結果顯示 HDGF 在細胞核的表現與病人是否受幽門螺旋桿菌感染 (p < 0.0001)、有無嗜中性白血球浸潤 (p = 0.0002) 及有無腸化生 (p < 0.0001) 具有相關性，在統計學上皆具有顯著差異。而進一步探討 HDGF 在胃癌中扮演的角色時，發現在外加 HDGF 重組蛋白刺激下，會使 AGS 細胞增生，及提高 AGS 細胞之移行能力，也會使得 EMT 相關轉錄因子 snail、 slug 及 twist 的表現量增加，鈣黏著素E (E-cadherin) 表現下降及中間絲蛋白 (vimentin) 的表現增加，進而誘導細胞 EMT 的發生。總結以上的研究得知，以幽門螺旋桿菌感染 AGS 細胞會誘導 HDGF 的表現及釋放，進而使癌細胞增生及藉由 EMT 的調控使癌細胞發生轉移。

Gastric carcinoma is one of the main causes of cancer death worldwide, especially in East and Southeast Asia, including Taiwan. Gastric cancer is the end result of a multifactorial, multistep process. Helicobacter pylori infection is a major risk factor in the development of gastric cancer. H. pylori causes a persistent infection in the human stomach, which can result in chronic gastritis, peptic ulcer disease and gastric cancer. However, the detailed mechanism of how H. pylori infection leads to the development of gastric cancer is still not clear. Particularly, the cellular factor(s) that contributes to H. pylori induced gastric carcinogenesis remains largely elusive. Hepatoma-derived growth factor (HDGF) is a novel growth factor involved in malignant progression of various types of cancer. HDGF overexpression is correlated with the proliferation state and lymph node metastasis of gastric cancer. The increased expression of HDGF is associated with poor prognosis of gastric cancers. Besides, HDGF regulates the invasiveness and epithelial–mesenchymal transition (EMT), which is critical to metastasis. Therefore, we investigate the expression profile of HDGF during H. pylori infection in AGS cells. In this study, we revealed that elevated HDGF expression and release higher in AGS cells after co-culture with H. pylori (ATCC 49503) than AGS cells. In immunohistochemical study, statistical analyses further revealed the nuclear HDGF expression was correlated positively with H. pylori infection (p < 0.0001), neutrophil infiltration (P = 0.0002), and intestinal metaplasia (p< 0.0001). Furthermore, adding exogenous HDGF treatment stimulated the proliferation, migration of AGS cells. HDGF treatment increased the EMT transcriptional factor (snail, slug, twist) expressions, as well as E-cadherin down-regulation and vimentin up-regulation of AGS cells. In summary, H. pylori infection of gastric epithelial cells induced the expression and release of HDGF, which might subsequently promote the tumorigenesis and metastasis of gastric cancer cells through modulation of EMT.

論文審定書 ------------------------------------------------------------------------------ i
致謝 --------------------------------------------------------------------------------------- ii
中文摘要 --------------------------------------------------------------------------------- iii
英文摘要 --------------------------------------------------------------------------------- v
目錄 -------------------------------------------------------------------------------------- vii
附表次/表次 ---------------------------------------------------------------------------- viii
附圖次/圖次 ----------------------------------------------------------------------------- ix
英文縮寫表 ------------------------------------------------------------------------------- x
第一章 前言 ---------------------------------------------------------------------------- 01
第一節 胃癌 -------------------------------------------------------------------------- 01
第二節 幽門螺旋桿菌與致病機制 ----------------------------------------------- 04
第三節 肝癌衍生生長因子 -------------------------------------------------------- 09
第四節 上皮-間質轉化 ------------------------------------------------------------- 11
第二章 研究動機 ----------------------------------------------------------------------- 13
第三章 研究架構 ----------------------------------------------------------------------- 14
第四章 材料與方法 -------------------------------------------------------------------- 15
第五章 結果 ----------------------------------------------------------------------------- 28
第六章 討論 ----------------------------------------------------------------------------- 35
第七章 結論 ----------------------------------------------------------------------------- 38
第八章 未來展望 ----------------------------------------------------------------------- 39
參考文獻 --------------------------------------------------------------------------------- 54
附表次/表次
附表一、 上皮細胞與間質細胞的分子標記及細胞特性 ----------------------- 12
表一、 評估 HDGF 蛋白質在胃部組織中的表現與臨床相關因子之關聯性 41
附圖次/圖次
附圖一、 導致胃癌的多重因子以及多重步驟 ---------------------------------- 03
附圖二、 幽門螺旋桿菌分解尿素中和胃酸的作用 ---------------------------- 05
附圖三、 VacA幫助幽門螺旋桿菌寄生在胃上皮細胞的途徑 --------------- 07
附圖四、 肝癌衍生生長因子結構圖 ---------------------------------------------- 10
圖一、 不同H. pylori與AGS細胞共同培養後之細胞型態 -------------------- 42
圖二、 AGS與H .pylori共同培養後之HDGF基因表現 ----------------------- 43
圖三、 AGS與H. pylori共同培養後之細胞內HDGF蛋白質表現 ------------ 44
圖四、 免疫螢光法分析AGS與H. pylori共同培養後HDGF蛋白質之表現 45
圖五、 AGS與H. pylori共同培養後之細胞上清液HDGF蛋白質的表現 46
圖六、 AGS 細胞受 H. pylori (ATCC49503) 感染後，釋放至細胞外的
HDGF 對細胞存活率的影響 ------------------------------------------------------- 47
圖七、 HDGF 對 AGS 細胞增生的影響 ----------------------------------------- 48
圖八、 HDGF 對 AGS 細胞移行能力分析 -------------------------------------- 49
圖九、 HDGF 對 AGS 細胞之 EMT 相關轉錄因子 mRNA 的影響 -------- 50
圖十、 HDGF對 AGS細胞之EMT相關分子標記 E-cadherin及vimentin
之 mRNA 的影響 ---------------------------------------------------------------- 51
圖十一、HDGF對 AGS細胞之EMT相關分子標記 E-cadherin及vimentin
之蛋白質的影響 ----------------------------------------------------------------- 52
圖十二、 利用免疫組織化學染色評估HDGF在胃部組織中的表現 -------- 53

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