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研究生:賴佩君
研究生(外文):Pei Chun Lai
論文名稱:探討Epstein-BarrNuclearAntigen1對鼻咽癌癌化之分子機制
論文名稱(外文):Role of the Epstein-Barr Nuclear Antigen 1 in the Oncogenesis of Nasopharyngeal Carcinoma
指導教授:趙玫趙玫引用關係
指導教授(外文):M. Chao
學位類別:碩士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:117
中文關鍵詞:EB病毒鼻咽癌
外文關鍵詞:EBVNPCEBNA1
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Epstein-Barr Virus (EBV)與鼻咽癌 (Nasopharyngeal carcinoma, NPC)在東南亞一帶包括台灣、香港、南中國等地區的發生關係密切,其中潛伏蛋白Epstein-Barr Nuclear Antigen 1 (EBNA1)在所有鼻咽癌檢體均可測得。依其胺基酸序列差異分型,原始型B95.8病毒株之EBNA1屬於P-ala亞型,鼻咽癌患者與台灣潛伏感染者之EBNA1皆屬於V-val亞型,依序簡稱為B-EBNA1、N-EBNA1與P-EBNA1。先趨實驗發現不同亞型EBNA1除了序列與大小上有所差異,穩定表達EBNA1之細胞株也具有程度不等的癌化能力,我認為這是不同EBNA1在調控細胞基因表現的能力不同所致,因此想進一步研究EBNA1對鼻咽癌癌化的分子機制。根據上述假說,我的實驗方向分為利用cDNA microarray分析轉錄層次上的差異,以及著重在與癌化相關之路徑和基因兩大部分探討。前者鎖定WNT訊號傳遞路徑,後者針對PI3K/Akt、MEK/Erk訊號傳遞路徑、腫瘤抑制因子p27與抵抗凋亡分子Mcl-1做研究。實驗結果發現:N-EBNA1與B-EBNA1會降低WNT負向調控因子ICAT的表現,活化下游基因MYC與slug,使細胞得以持續生長;E-cadherin和β-catenin在N-EBNA1與B-EBNA1細胞膜上的點狀分布,暗示著細胞彼此間附著力下降,轉移能力上升。第二部分在N-EBNA1與B-EBNA1細胞株中,p27蛋白質的低表現量與Akt分子無直接關係;Mcl-1的蛋白質表現量上升但mRNA層次差異不大,推測與轉譯後調控有關。以上在在顯示EBNA1是一個腫瘤誘導因子,並且可能藉由上述調控方式使細胞走向癌化,而了解EBNA1在鼻咽癌癌化過程所扮演的角色,對日後研究與治療必有莫大助益。
Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC) which is a common malignant disease in areas of Taiwan, Hong Kong and southern China. Moreover, the Epstein-Barr Nuclear Antigen 1 (EBNA1) is the latent viral protein consistently detected in all NPC in Southeast Asia. Based on the amino acid sequences, the EBNA1 of B95.8 strain, namely B-EBNA1, is defined as P-ala subtype, while the majority of EBNA1 subtype in Taiwan is V-val, both in NPC and general population. The latter two have different sizes, and are referred to as N-EBNA1 and P-EBNA1, respectively. Previous data from the lab showed that the various clones of EBNA1 have different effect on cell growth and survival. I thereby hypothesized that different EBNA1s transactivate cellular genes differently. To confirm this hypothesis, I performed transcriptional profiling analysis of EBNA1-expressing cells by cDNA microarray analysis and focused on those genes associated with pathways affecting tumor formation. Many genes in the WNT signaling pathway were aberrantly expressed in cells expressing N-EBNA1. Furthermore, the roles of genes involved in PI3K/Akt and MAPK/Erk pathways, the tumor suppressor p27, and the anti-apoptotic BCL-2 family member Mcl-1 in NPC oncogenesis were also examined. The results show that (i) N-EBNA1 and B-EBNA1 decrease transcription of the Wnt inhibitor ICAT and increase transcription of both WNT target genes, MYC and slug, which might contribute to the cell survival; (ii) E-cadherin-β-catenin complexes colocalize on cell surface and appear as “spot-like” structures in cells expressing N-EBNA1 and B-EBNA1, which might accompany the loss of E-cadherin-dependent cell-cell adhesions and promote cell migration; (iii) The expression of p27 is decreased in cells expressing N-EBNA1 and B-EBNA1, which is not associated with Akt pathway; (iv) Mcl-1 mRNA levels remain constant while its protein levels are reduced in cells expressing N-EBNA1 and B-EBNA1. The data suggested that EBNA1 may influence a number of cellular functions which may contribute to the development of NPC.
指導教授推薦書………………………………………………………
口試委員會審定書……………………………………………………
長庚大學授權書………………………………………………………iii
誌謝……………………………………………………………………iv
中文摘要………………………………………………………………v
英文摘要………………………………………………………………vi
目錄……………………………………………………………………vii
圖表目錄………………………………………………………………xi
第一章序論……………………………………………………………1
第二章材料與方法……………………………………………………28
第三章實驗結果與討論………………………………………………36
第四章結論……………………………………………………………53
參考文獻………………………………………………………………60
附錄……………………………………………………………………79

圖一 EB病毒基因體構造………………………………………………79
圖二 EB病毒的生活史…………………………………………………80
圖三 EBNA1結構與功能示意圖………………………………………81
圖四 EBNA1亞型序列比較……………………………………………82
圖五 WNT訊號傳遞路徑………………………………………………83
圖六 p27的轉錄後調控作用…………………………………………84
圖七 不同來源EBNA1在序列與大小上有所差異……………………85
圖八 實驗方向流程圖…………………………………………………86
圖九 N-EBNA1與Neo細胞株之間具顯著差異基因的細胞功能分布…………………………………………………………………………87
圖十 N-EBNA1與Neo細胞株WNT訊號傳遞路徑微陣列比較分析………………………………………………………………………88
圖十一 ICAT mRNA在細胞中的表現量差異…………………………89
圖十二 Myc mRNA在細胞中的表現量差異…………………………90
圖十三 Slug與E-cadherin在細胞中的表現量差異…………………91
圖十四 β-catenin在細胞中的表現量差異……………………………92
圖十五 β-catenin在細胞中的轉錄活化能力…………………………93
圖十六 E-cadherin與β-catenin在細胞中的分布情形……………94
圖十七 PI3K/Akt訊號傳遞路徑上游分子在細胞中的表現量差異…95
圖十八 Erk 1/2分子在細胞中的表現量差異…………………………96
圖十九 p27在細胞中的分布情形………………………………………97
圖二十 p27在細胞中的表現量差異……………………………………98
圖二十一 Mcl-1在細胞中的表現量差異………………………………99
表一 不同EBNA1 clones對細胞功能之影響…………………………100
表二 網路介面BABELOMICS群組基因…………………………………101
表三 網路介面Invitrogen iPath群組分類排名………………………102
表四 WNT訊號傳遞路徑在有無表達EBNA1細胞中之表達差異基因列表…………………………………………………………………………103
表五 CDC42生物功能與PI3K/Akt訊號傳遞路徑在有無表達EBNA1細胞中之表達差異基因列表…………………………………………………………104
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