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研究生:黃金仁
論文名稱:以微陣列分析法探討猿病毒腫瘤抗原氮端區段抑制神經膠原致癌基因表現之分子機轉
論文名稱(外文):Microarray approach toward the molecular mechanism of transcriptional suppression of HER2/neu by the N-terminal domain of SV40 large Tantigen
指導教授:高銘欽高銘欽引用關係
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:80
中文關鍵詞:神經膠原致癌基因猿病毒腫瘤抗原氮端區段維甲酸受體微陣列維甲酸誘導基因
外文關鍵詞:HER2/neuSV40 LT425RARMicroarrayRIG1
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神經膠原致癌基因調控失常而致過度表現常引起許多人類的癌症,臨床報告顯示其與癌細胞轉移與預後不良有密切的關係。本實驗室之前證實猿病毒腫瘤抗原氮端1-178個胺酸部位 (猿病毒腫瘤抗原氮端區段 LT425) 在神經膠原致癌基因過度表現的卵巢癌及乳癌細胞中能有效作為腫瘤轉形的抑制劑。然而,對於猿病毒腫瘤抗原氮端區段抑制神經膠原致癌基因過度表現的機轉仍不清楚。本論文採用微陣列分析法試圖找出與猿病毒腫瘤抗原氮端區段抑制神經膠原致癌基因過度表現相關的基因。經微陣列實驗結果顯示共有1685個基因表現增加,而有114個基因表現降低,其中經文獻交叉搜尋比對結果發現RARRES3基因有可能參與猿病毒腫瘤抗原氮端區段抑制腫瘤生長的作用,西方墨點實驗也證實此項推測,因此,本論文提出初步假說如下:猿病毒腫瘤抗原氮端區段可能直接活化RARRES3基因而引發腫瘤抑制效應,或者也可能經由活化維甲酸胞核受體後再活化RARRES3基因而引發腫瘤抑制效應。

It has been known that HER2/neu is overexpressed in a wide variety of human cancers and shown to be associated with increased metastasis and poor prognosis. We have demonstrated that the N-terminal domain of SV40 large T antigen (LT425) can act as a transforming suppressor of the HER2/neu oncogene in human ovarian and breast cancer cells. However, the repression mechanism of HER2/neu by LT425 is still unknown In this study, by using the microarray approach, we have made an attempt at finding genes related to the suppression of HER2/neu by LT425. Among 6000 known human genes, 1685 genes were found to be up-regulated while 114 genes were down-regulated in LT425-transfected ovarian cancer cells. In addition, through the microarray data comparison and related literature search, the RARRES3 gene was demonstrated to be the most possible one which involves in the LT425-mediated transcriptional repression of HER2/neu oncogene. The elevated level of RARRES3 protein in LT425-transfeced ovarian cancer cells was further elucidated by Western blot analysis. Therefore, a preliminary hypothesis was proposed that LT425 may directly activate the expression of RARRES3 gene leading to the repression of HER2/neu oncogene. It may also be possible that LT425 stimulates the binding of RAR with RA followed by activating RARRES3 gene expression and causes tumor suppressing effects.

目 錄
目錄………………………………………………………………………….……..Ⅰ
表目錄………………………………………………………………………….…..Ⅲ
圖目錄…………………………………………………………………….………..Ⅳ
縮寫表……………………………………………………………………….……..Ⅴ
中文摘要…………………………………………………………………….……..Ⅵ
英文摘要…………………………………………………………………….……..Ⅶ
第一章、 緒論
壹、 神經膠原致癌基因……………………………………….….……..1
貳、 神經膠原致癌基因與癌症………………………………..………..3
參、 目前針對HER2/neu的治療方法…………………………..……...4
肆、 猿病毒腫瘤抗原……………………………………………..……..7
伍、 微陣列分析……………………………………………….….……..8
陸、 維甲酸細胞核受體……………………………………….….…….10
柒、 TIG3/RIG1基因之發現及相關研究…….……………….….……14
捌、 研究背景及目的………………………..………………….….…...15
第二章、 材料與方法………………………………...…………………..………16
第一節、 實驗材料與儀器………………………………………….………..16
壹、 細胞株…………………………………………………….………..16
貳、 抗體……………………………………………………….………..16
參、 化學藥品試劑與其他耗材……………………………….………..16
肆、 儀器………………………………………………………….……..17
第二節、 實驗方法…………………………………………………….……..18
壹、 細胞解凍及處理…………………………………………………..18
貳、 總量RNA抽取………………………...……………………...….23
參、 微陣列分析實驗………………………………………….……….24
肆、 蛋白質萃取…………………………………………………..........27
伍、 蛋白質濃度測定………………………………………………......28
陸、 西方墨點法………………………………………………………..28
柒、 維甲酸處理細胞及檢測RAR核受體與TIG3/RIG1之蛋白表
現量………………………………………………………………..30
第三章、 結果……………………………………………………………….…...32
壹、 以Trizol方法抽取RNA………………………………………….32
貳、 微陣列資料分析……………………….……………………….…32
參、 RARRES3 (TIG3) 基因之篩選,研究及初步假說……….…….33
肆、 以西方墨點法測定RIG1/TIG3在卵巢癌細胞中蛋白質表現量.34
伍、 以西方墨點法測定RAR-β在卵巢癌細胞中蛋白質表現量…...34
陸、 以西方墨點法測定RAR-α在卵巢癌細胞中蛋白質表現量…...35
柒、 以西方墨點法測定caspase-3在卵巢癌細胞中蛋白質表現量…35
第四章、 討論……………………………………………………………………36
第五章、 結論……………………………………………………………………42
表…………………………………………………………………………………..43
圖…………………………………………………………………………………..47
參考文獻…………………………………………………………………………..55
附錄一……………………………………………………………………………..63
附錄二……………………………………………………………………………..72
表目錄
表一、 SKOV3.ip1卵巢癌細胞在穩定轉染LT425基因後經微陣列測定
比較基因表現量大於或等於1.95的基因……………………………..43
表二、 SKOV3.ip1卵巢癌細胞在穩定轉染LT425基因後經微陣列測定
分析比較基因表現量小於0.5的基因…………………………………44
表三、 在SKOV3.ip1-LT425-29及SKOV3.ip1-LT425-31兩個細胞株中
接受LT425上升調控的微陣列分析結果……………………………..45
表四、 HER2/neu、LT425與TIG3/RIG1之間的相互關聯性…...…………...46
圖目錄
圖 2-1. 實驗流程圖……………………………………………………………….47
圖 3-1. 利用Trizolz方法抽取RNA後之電泳圖……………………..……..….48
圖 3-2. LT425抑制HER2/neu之初步假說………..………….…………….…...49
圖 3-3. 以西方墨點法分析 p185 及 RIG 1 於卵巢癌細胞珠中的表現….…..50
圖 3-4. 以西方墨點法分析 p185 及 RAR-β 於卵巢癌細胞珠中的表現…...51
圖 3-5. 以西方墨點法分析p185與RAR-α 於卵巢癌細胞珠中的表現……..52
圖 3-6. 以西方墨點法分析caspase-3 於卵巢癌細胞珠中的表現………...…...53
圖 3-7. 根據本論文實驗結果提出LT425抑制HER2/neu基因表現之假說.....54

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