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標題: | 鑑定Annexin A4 為胃癌新穎分子標記並探討其於
幽門螺旋桿菌感染後膜修復的角色 Identification of annexin A4 as a novel molecular marker for gastric cancer and elucidation of its role in membrane repair after Helicobacter pylori infection |
作者: | Li-Ling Lin 林俐伶 |
指導教授: | 阮雪芬(Hsueh-Fen Juan) |
關鍵字: | Annexin A4,幽門螺旋桿菌,胃癌,膜修復,細胞增殖, Annexin A4,H. pylori,Gastric cancer,Membrane repair,Cell proliferation, |
出版年 : | 2010 |
學位: | 博士 |
摘要: | 幽門螺旋桿菌是一種常見的人類病原菌,也是第一個被正式承認可作為致癌物質的細菌,它與導致胃癌有關。在這個研究中,我們利用蛋白質體學的研究方法找出,在感染幽門螺旋桿菌病人的正常組織和腫瘤組織間有表現量差異的蛋白質。其中,我們發現annexin A4在有幽門螺旋桿菌感染的腫瘤組織及胃癌細胞中表現量增加,在免疫組織化學染色的胃癌組織中其表現量亦較正常組織高。藉由同源模擬法來預測人類annexin A4的結構,則發現預測的結構與已知的牛的結構(PDB code, 1ANN)相比,有相同的鈣離子結合位置。前人的研究中指出,幽門螺旋桿菌的感染會活化interleuken-8 (IL-8)的表現,而在我們的結果中顯示,幽門螺旋桿菌感染後,IL-8的表現會被annexin A4的小型干擾核糖核酸所抑制,所以結合這些結果我們知道,在感染幽門螺旋桿菌的胃癌細胞中,annexin A4的表現量增加可能會促使IL-8的表現,而IL-8的表現則已知會導致血管新生的形成。除此之外,因為有報導指出annexins與細胞膜修復有關,所以,我們進一步探討annexin A4在胃幽門螺旋桿菌感染後與細胞膜修復及其所誘導的訊號傳遞路徑中所扮演的角色。細胞膜修復是細胞在面對機械性的壓力及病原體時,為了生存所產生的普遍反應。然而,對於幽門螺旋桿菌的感染會與宿主細胞膜修復的相關性的了解很少。在我們的結果中顯示,幽門螺旋桿菌會破壞宿主細胞膜並誘導鈣離子流的進入,進而使得細胞中的annexin家族成員A1和A4移動位置到細胞膜。接著,藉由募集溶酶體膜和誘導下游信號的傳遞以活化膜的修復反應,以致於細胞得以存活並導致細胞的增殖。基於這些結果,我們提出了一個新的模型,幽門螺旋桿菌的感染會激活annexin A1和A4對於細胞膜的修復反應,接著annexin A4的表現量增加會誘導信號分子而促進細胞增殖;然而,保持這種活化可能使細胞進入不正常的狀態,並導致癌變。本研究鑑定annexin A4為新穎的胃癌分子標記且連結幽門螺旋桿菌感染到細胞膜的修復,就細胞膜損傷可能引起的癌變機制提供了新的想法。 Helicobacter pylori is one of the most common human pathogens and the first formally recognized bacterial carcinogens associated with gastric cancer. In this study, we used a proteomics approach to discover differentially expressed proteins between normal and tumor tissues in gastric cancer patients infected with H. pylori. We found that annexin A4 was over-expressed in patients infected with H. pylori and in gastric cancer cells after H. pylori infection. We also found the same results for gastric cancer tissues by immunohistochemical staining. Through homology modeling, human annexin A4 was predicted to have the same Ca2+ binding site as several proteins with known bovine structures (PDB code, 1ANN). Previous studies have shown that interleuken-8 (IL-8) expression could be activated by H. pylori infection. In our results, IL-8 expression was inhibited by annexin A4-specific siRNA after infection. Combining these results, over-expression of annexin A4 in H. pylori-infected cells may subsequently induce IL-8, which has been found to cause tumor angiogenesis. Additionally, reports have found that annexins are associated with cell membrane repair. Thus, we investigated the role of annexin A4 in membrane repair and the downstream signal transduction pathway after H. pylori infection. Membrane repair is a universal response against physical and biological insults and enables cell survival. However, little is known about host membrane repair in the context of H. pylori infection. In our results, H. pylori disrupted the host plasma membrane and induced Ca2+ influx, which triggers the translocation of annexin family members A1 and A4 to the plasma membrane. This in turn activates a membrane repair response through the recruitment of lysosomal membranes and the induction of downstream signaling transduction pathways that promote cell survival and proliferation. Based on our data, we propose a new model by which H. pylori infection activates annexin A1 and A4 for membrane repair and how annexin A4 over-expression induced signaling promotes cell proliferation. However, continual activation of this membrane repair response signaling cascade may cause abnormal cellular states leading to carcinogenesis. This study identifies annexin A4 as a novel molecular marker for gastric cancer and links H. pylori infection to membrane repair, providing insight into potential mechanisms of carcinogenesis resulting from membrane damage. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48691 |
全文授權: | 有償授權 |
顯示於系所單位: | 分子與細胞生物學研究所 |
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