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研究生:黃國真
研究生(外文):Gwo-Jen Huang
論文名稱:3OST3B與CDH3基因於台灣乳癌檢體組織之甲基化變異及基因功能分析
論文名稱(外文):The 3OST3B and CDH3 Promoters Aberrant Methylation and Gene Function Studies in Taiwan Clinical Breast Cancer Tissues
指導教授:陳小玲陳小玲引用關係陳全木陳全木引用關係
指導教授(外文):Hsiao-Ling ChenChuan-Mu Chen
學位類別:碩士
校院名稱:大葉大學
系所名稱:分子生物科技學系碩士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:136
中文關鍵詞:胎盤神經鈣黏蛋白基因硫酸乙醯肝素糖胺聚糖硫基轉移酶基因結合亞硫酸鈉化學修飾與限制酶分析DNA甲基化乳癌
外文關鍵詞:CDH33OST3BDNA MethylationCOBRAbreast cancer
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台灣女性乳癌死亡率逐年攀升,殊值關注。形成乳癌的危險因子繁多,除了家族遺傳、內分泌因子與外在環境的致癌因子外,腫瘤抑制基因及生長調節相關基因之基因啟動子區域的異常甲基化,所導致之基因表現異常亦與乳癌生成息息相關。本論文遂以研究基因啟動子區域的異常甲基化和乳癌生成的關係為主軸。針對76個乳癌病患檢體組織之細胞膜外的黏附因子胎盤神經鈣黏蛋白基因CDH3及調控膜外蛋白之硫酸乙醯肝素糖胺聚糖硫基轉移酶基因3OST3B,做基因甲基化異常修飾及其功能分析分析。首先利用甲基化特異性聚合酶連鎖反應(MS-PCR)、結合亞硫酸鈉化學修飾與限制酶分析(COBRA)等技術分析CDH3及3OST3B啟動子區域的甲基化狀態。由於在CDH3之甲基化分析中無法觀察到甲基化現象,故僅選擇3OST3B 進行後續實驗,採用亞硫酸鈉核酸化學修飾定序分析(bisulfite-sequencing)、反轉錄聚合酶連鎖反應(RT-PCR)、免疫組織化學染色(IHC)等技術探討3OST3B於臨床乳癌檢體中甲基化CpG小島分佈及mRNA與蛋白質表現情形。試驗結果可將76位乳癌病患分為低度(27位)、中度(20位)及高度(29位)甲基化三族群,且在3OST3B基因啟動子區域內可搜尋到主要作用之轉錄因子,包括了NF-κB、E2F及n-MYC,這些轉錄因子的結合區皆包含了CpG雙核苷酸,一旦發生甲基化之現象可能會影響上述轉錄因子結合而影響3OST3B基因的表現。並由IHC觀察到3OST3B高度甲基化之病理切片中腫瘤組織之3OST3B的表現量較低,而高度甲基化乳癌細胞株(MDA-MB-231)經去甲基化藥劑5-azadC處理後,結果顯示可降低3OST3B甲基化程度並回復3OST3B mRNA及蛋白質的表現。在臨床病理資料的統計中可觀察到,當3OST3B為中、高度甲基化時,與不具遠端轉移(M0)及p53表現較高的乳癌病患族群,具有統計顯著之相關性,因此,3OST3B可能是一個有意義的基因,可作為乳癌風險評估的一個指標。
The death rate of breast cancer in Taiwan has obviously risen these years, which becomes a very important issue. Many risk factors such as aberrant DNA methylation of promoter region of tumor suppress gene and growth-related gene have been reported, besides family history of breast cancer, endocrine, and carcinogen. Therefore, this study was focused on the relation between aberrant DNA methylation in gene promoter region and breast cancer tumorigenesis. Tumor and normal tissues obtained from 76 breast cancer patients were used to analyze the methylation status of promoter region and gene expression in both of cell membrane protein gene-P-cadherin (CDH3) and regulatory extracellular matrix glycoprotein gene-heparan sulfate D-glucosaminyl 3-O-sulfotransferase (3OST3B) by methylation specific PCR(MS-PCR) and combined bisulfite restriction analysis (COBRA). Because there was no aberrant methylation observed in CDH3, only 3OST3B was chosen for further analyses including COBRA- sequencing, reverse transcription PCR (RT-PCR), and immunohistochemical stain (IHC). The distribution of methylated CpG site and the expression of mRNA and protein were analyzed. According to the methylation status of 3OST3B in the tumor tissues, we divided the 76 patients into three groups- 27 patients of hypomethylation, 20 patients of intermedium-methylation and 29 patients of hypermethylation. In 3OST3B promoter region, there were many CpG dinucleotides found in the binding sites of several transcription factors such as NF-κB, E2F, and n-MYC. The methylation status of CpG dinucleotides might affect the expression of 3OST3B. The results of IHC showed that the expression of 3OST3B in tumor tissues with 3OST3B hypermethylation were lower than in normal tissues. After the treatment of demethylation agent, 5-azadC, in breast cancer cell line MDA-MB-231, the methylation level of 3OST3B decreased and the gene expression was restored. The association of 3OST3B methylation status with clinicopathological features of patients with breast cancer showed that 3OST3B with intermedium-methylation and hypermethylation was significantly correlated with non-metastasis (M0) and high p53 expression. Therefore, 3OST3B could be a valuable candidate gene as a predictor of breast cancer risk assessment.
目 錄

封面內頁
簽名頁
授權書........................................... .....iii
中文摘要..................................... .........iv
英文摘要................................ ..............vi
誌謝............................ .....................viii
目錄................................... ...............ix
圖目錄................................. ..............xiv
表目錄...............................................xvii


第一章 緒言............................................1
第二章 文獻檢討........................................3
2.1 乳癌簡介..........................................3
2.1.1 台灣女性乳癌之好發率統計......................3
2.1.2 乳房的基本構造................................7
2.1.3 乳癌之形成....................................9
2.1.4 易造成乳癌的危險因子..........................9
2.1.5 乳癌的分類...................................12
2.1.6 乳癌的分期...................................13
2.1.7 乳癌常用的治療方法...........................13
2.2 DNA甲基化修飾與基因活性的調節...................14
2.3 乳癌中常見甲基化之腫瘤抑制基因及生長調節基因....19
2.3.1 類固醇感受器基因甲基化對乳癌的影響..........20
2.3.2 BRCA1 甲基化和偶發性乳癌之關係.............21
2.3.3 CDH1 甲基化與乳癌之關係....................22
2.4 鈣黏蛋白和乳癌的關係.............................23
2.4.1 鈣黏蛋白簡介................................23
2.4.2 鈣黏蛋白在乳癌中的表現.....................24
2.4.3 CDH1及CDH3在乳癌細胞中之表現............25
2.5 生物體中硫酸乙醯肝素糖胺聚糖扮演之功能..........27
2.5.1 硫酸化的重要性..............................27
2.5.2 細胞膜外結構之硫酸化........................30
2.5.3 硫酸乙醯肝素在細胞表面的訊息傳遞............34
2.5.4 HSGAG在癌症中所扮演的角色..................35
第三章 利用甲基化特異性PCR分析CDH3基因於乳癌檢
體組織甲基化之狀態..............................37
3.1 前言............................................37
3.2 材料與方法......................................37
3.2.1 乳癌病患檢體之取得與保存....................37
3.2.2 乳房腫瘤組織DNA萃取.......................38
3.2.3 對照組DNA甲基化處理.......................39
3.2.4 DNA之亞硫酸鈉化學修飾......................40
3.2.5 MS-PCR分析.................................40
3.3 結果與討論......................................44
第四章 乳癌檢體組織中3OST3B基因調節區域的甲基化
狀態與基因表現之分析...........................49
4.1 前言............................................49
4.2 材料與方法......................................49
4.2.1 乳房腫瘤組織DNA萃取及DNA之亞硫酸鈉
化學修飾....................................49
4.2.2 結合亞硫酸鈉化學修飾與限制酶分析............50
4.2.3 亞硫酸鈉化學修飾核酸定序分析................55
4.2.4 萃取乳房腫瘤組織RNA........................57
4.2.5 反轉錄聚合酶連鎖反應........................58
4.2.6 乳癌組織檢體切片之3OST3B組織免疫呈色分析..59
4.2.7 臨床資料之統計分析..........................60
4.3 結果與討論......................................61
4.3.1 利用COBRA技術及COBRA核酸定序分析
3OST3B調節區域之CpG小島甲基化狀態........61
4.3.2 利用IHC分析乳癌檢體組織病理切片中
3OST3B之表現..............................70
4.3.3 臨床病理資料統計分析........................74
第五章 乳癌細胞株之3OST3B甲基化分析及去甲基化試驗...77
5.1 前言............................................77
5.2 材料與方法......................................78
5.2.1 乳癌細胞株之取得與保存......................78
5.2.2 萃取乳癌細胞株DNA.........................79
5.2.3 DNA之亞硫酸鈉化學修飾及結合亞硫酸鈉化學
修飾與限制酶截切酵素分析....................80
5.2.4 萃取乳房腫瘤組織與乳癌細胞株RNA............80
5.2.5 反轉錄聚合酶連鎖反應........................80
5.2.6 去甲基化藥物處理............................80
5.2.7 北方點墨法..................................81
5.2.8 乳癌細胞株3OST3B蛋白表現之分析............83
5.2.9 SDS-PAGE分析...............................84
5.2.10 西方點墨法.................................85
5.3 結果與討論......................................87
5.3.1 COBRA 分析人類乳癌細胞株、肺癌細胞株及
肝癌細胞株之3OST3B甲基化狀態..............87
5.3.2 乳癌細胞株經去甲基化藥劑處理後3OST3B甲
基化變異...................................89
5.3.3 乳癌細胞株經去甲基化藥劑處理後3OST3B
mRNA表現.................................89
5.3.4 乳癌細胞株MCF7及MDA-MB-231之3OST3B表
現量分析...................................93
第六章 乳癌細胞株表現3OST3B及其功能分析.............95
6.1 前言............................................95
6.2 材料與方法......................................96
6.2.1 3OST3B-pIRES2-dsRed2載體之構築..............96
6.2.2 3OST3B-pIRES2-DsRed2轉染於MDA-MB-231
細胞株.....................................103
6.3 結果與討論.....................................104
6.3.1 3OST3B構築於pIRES2-DsRed2表現載體之分析....104
6.3.2 3OST3B-pIRES2-DsRed2轉染於MDA-MB-231
細胞株之分析..............................107
第七章 結論..........................................115
參考文獻.............................................118



















圖 目 錄

圖2-1、行政院衛生署九十三年度歷年死亡統計..............4
圖2-2、行政院衛生署女性乳癌及子宮頸癌死亡率暨年齡
別死亡率統計....................................8
圖2-3、成熟女性乳房解剖圖..............................9
圖2-4、液下淋巴結分佈圖...............................11
圖2-5、胞嘧啶的甲基化添加.............................16
圖2-6、DNA甲基化修飾可引發組蛋白甲基化修飾作用......18
圖2-7、硫酸基轉移酶之催化機制.........................29
圖2-8、HSGAG的生合成................................32
圖2-9、HSGAG的結構和生物性質........................33
圖3-1、甲基化與未甲基化DNA模板經亞硫酸鈉化學修飾之
DNA序列形態.................................42
圖3-2、CDH3調節區至exon I CpG小島分佈位置暨MS-PCR
引子設計位置、引子的序列、擴增區大小與接合溫度
條件..........................................43
圖3-3、14對乳癌病患檢體組織DNA其CDH3之MS-PCR分
析結果........................................46
圖3-4、14個乳房腫瘤組織DNA其CDH3之MS-PCR分析
結果..........................................47
圖3-5、乳癌細胞株HS578t、MDA-MB-468、MDA-MB-231
DNA其CDH3之MS-PCR分析結果................48
圖4-1、COBRA原理暨計算甲基化計算之方法..............51
圖4-2、甲基化敏感性限制酶BstUI之截切位置與切出片段
大小..........................................53
圖4-3、乳癌病患檢體組織之3OST3B COBRA-PCR產物.....64
圖4-4、乳癌病患檢體組織之3OST3B COBRA分析..........65
圖4-5、3OST3B依據COBRA定量分析所定義之低度、中
度與高度甲基化之族群...........................66
圖4-6、COBRA-PCR擴增產物之分子選殖.................67
圖4-7、乳癌檢體組織含低、中、高度甲基化程度之
COBRA-PCR定序結果與核酸序列比對............68
圖4-8、COBRA核酸定序分析3OST3B啟動子區域之甲基
化狀態........................................69
圖4-9、免疫組織化學呈色分析乳癌病患乳房組織之3OST3B
蛋白表現......................................72
圖4-10、免疫組織化學呈色分析乳癌檢體不同部位乳房組織
切片之3OST3B表現............................73
圖4-11、癌細胞遠端轉移及p53表現狀態與3OST3B甲基化
程度之統計圖..................................76
圖5-1、經亞硫酸鈉化學修飾人類乳癌細胞株、肺癌細胞株
及肝癌細胞株之3OST3B COBRA分析.............88
圖5-2、經去甲基化藥劑處理乳癌細胞株MDA-MB-231,
3OST3B甲基化狀態及RNA表現分析................91
圖5-3、利用北方點墨法分析去甲基化藥劑未處理與處理乳
癌細胞株之3OST3B mRNA表現量...................92
圖5-4、3OST3B於乳癌細胞株中總蛋白及細胞質蛋白之表現
差異分析.......................................94
圖6-1、3OST3B全長序列選殖............................108
圖6-2、E. coli DH5α質體DNA中3OST3B全長序列進行
核酸定序分析確認及所轉譯出之胺基酸序列........109
圖6-3、篩選出之3OST3B完整全長序列與NCBI中原始
3OST3B完整全長序列比對.......................111
圖6-4、篩選出之3OST3B胺基酸全長序列與NCBI中原
始3OST3B胺基酸完整全長序列比對..............112
圖6-5、pIRES2-DsRed2表現載體及3OST3B構築的相對
位置..........................................113
圖6-6、3OST3B構築於pIRES2-DsRed2表現載體...........114













表 目 錄

表2-1、行政院衛生署九十二年度台灣地區主要癌症死亡
統計............................................5
表2-2、行政院衛生署女性乳癌及子宮頸癌死亡率統計........6
表4-1、乳癌檢體中3OST3B啟動子區域甲基化狀態與臨
床病理資料之統計分析...........................75
行政院衛生署九十二年度癌症死亡統計。台灣
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