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研究生：	蔡瑞和 Tsai, Jui-He
論文名稱：	以微矩陣基因晶片探討細胞經紫外線照射後之基因表現 Application of cDNA microarray on studies of UVC-induced cell’s gene expressions
指導教授：	黃溫雅 Huang, Wenya 張憲彰 Chang, Hsien-Chang
學位類別：	碩士 Master
系所名稱：	工學院 - 醫學工程研究所 Institute of Biomedical Engineering
論文出版年：	2002
畢業學年度：	90
語文別：	中文
論文頁數：	93
中文關鍵詞：	核酸切除修復、GADD45A 、GADD153 、微矩陣基因晶片
外文關鍵詞：	microarray, GADD45A, GADD153, NER
相關次數：	點閱：89 下載：1
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　　微矩陣基因晶片技術的發展使得科學家可以快速的檢測細胞內整體基因的表現。對於基因之間互相影響的關係可更正確快速的定義。本實驗之目的為了解一些核酸切除修復(NER)因子之功能與其影響之下游基因，故使用HeLa細胞(核酸切除修復正常)與著色性乾皮症病人細胞所作成的細胞株~XPC (XP4PA-SV)細胞(核酸切除修復缺失)進行比較。將細胞照射紫外線(254 nm)後再給予不同的培養時間讓其進行修復，之後抽取細胞之mRNA進行微矩陣基因晶片檢測。再使用ScanAlyze 2程式(史丹佛大學Partick O. Brown研究室發展)將晶片上的訊號強度定量，最後用Principal component analysis (PCA)統計方法分析，此統計方法可將相同表現趨勢的基因歸納為群組(factor)，每一群組中的基因再利用t-test分析而判知其基因表現趨勢。研究中每個實驗組皆使用3片晶片，如此可除去偽陽性訊號，且只有顯示機率(p)小於0.05的基因才是確實的結果。這些基因會再用反轉錄聚合酶連鎖反應(RT-PCR) 再次印證其基因表現。
　　經由PCA分析後，可得到4個基因表現趨勢不同的群組(factors)，每個群組中包含2-4個基因。在這些基因中，發現growth arrest and DNA-damage-inducible 153 (GADD153)與growth arrest and DNA-damage-inducible 45, alpha (GADD45A)在與XP4PA-SV細胞HeLa細胞經紫外線照射後有不同的基因表現。再使用RT-PCR進一步的分析其它NER正常與缺失的細胞，結果發現GADD153在HeLa細胞與XPC細胞所表現出的差異，並不是因為DNA修復功能有差異而導致此現象。在GADD45A的基因表現方面，NER缺失的細胞照射完紫外線30分鐘後就有快速上升表現的現象，而在NER正常的細胞中則是較晚才有上升表現。推測可能是因為細胞中某些修復蛋白功能有問題，使得細胞內的GADD45A有代償作用而在早期上升表現，以使得細胞能夠盡其所能的去修復其損傷。

　　DNA microarray technology allows scientists to detect global gene expressions of cells. The goal of this research project is to understand the functions of nucleotide excision repair (NER) factors and the genes that they regulate. The HeLa cells (NER proficient) and XPC mutant cells (NER deficient) were subjected to studies of the responses to post-UVC irradiation by cDNA microarray. The cellular mRNAs from both cell lines were isolated and hybridized to the genes on the cDNA chip. The signals were quantitated by the software ScanAlyze 2 (developed by Brown, C. A.). For statistical analysis microarray data, each experimental condition was performed in triplicates. Principal component analysis (PCA) was then applied to identify genes whose expressional changes were associated. The gene expression changes were also confirmed by the t-test analysis as well as RT-PCR on each individual gene.

　　By PCA, four major expression patterns were identified, depending on the directionality of expression changes in each gene from the control to various lengths of post-UVC incubation. We found that the expressions of growth arrest and DNA-damage-inducible 153 (GADD153) and growth arrest and DNA-damage-inducible 45, alpha (GADD45A) different in the HeLa cells and XP4PA-SV cells. The GADD153 and GADD45A expressions in other NER proficient and deficient cells were also examined. We found that expression levels of the GADD153 gene did not show a strong correlation with in vivo NER activity. In the case of the GADD45A gene, it was up-regulated in the XPC cells 30 minutes after the UVC irradiation; however, it was induced much later in the NER proficient cells. Besides XPC cells, the NER deficient XPA cells also demonstrated the early induction of the GADD45A gene. It is concluded that the expression of GADD45A gene is immediately activated in these XP cells.

中文摘要 ----------------------------------------------------------------- I
英文摘要 ----------------------------------------------------------------- II
誌謝 --------------------------------------------------------------------- III
目錄 --------------------------------------------------------------------- IV
表目錄 ------------------------------------------------------------------- VII
圖目錄 ------------------------------------------------------------------- VIII
公式&符號----------------------------------------------------------------- X
縮寫表 ------------------------------------------------------------------- X


第一章 緒論 --------------------------------------------------------------  1
 1.1 前言 ----------------------------------------------------------------  1
 1.2 基因修復機制 --------------------------------------------------------  1
 1.3 紫外線對DNA之傷害 ---------------------------------------------------  3
    1.3.1 環丁烷嘧啶雙體(cyclobutane pyrimidine dimers) ------------------  3
    1.3.2 6-4嘧啶光產物(6-4 photoproducts) -------------------------------  4
 1.4 核酸切除修復(nucleotide excision repair) ----------------------------  5
    1.4.1 整體基因修復(GGR) ----------------------------------------------  5
    1.4.2 轉錄偶合修復(TCR) ----------------------------------------------  6
 1.5 著色性乾皮症(xeroderma pigmentosum syndrome) ------------------------  7
 1.6 微矩陣基因晶片(microarray)之原理與應用論文回顧 ---------------------- 10
 1.7微矩陣基因晶片之檢測方法 --------------------------------------------- 12
 1.8基因晶片的應用 ------------------------------------------------------- 13
    1.8.1 基因定序 ------------------------------------------------------- 13
    1.8.2 cDNA晶片之於偵測基因表現程序 ----------------------------------- 14
    1.8.3 cDNA晶片之於細胞癌化的檢測 ------------------------------------- 15
    1.8.4 cDNA晶片之於藥物篩選與毒物分析 --------------------------------- 15
 1.9 論文回顧 ------------------------------------------------------------ 17
 1.10 研究動機 ----------------------------------------------------------- 18
 1.11 研究架構 ----------------------------------------------------------- 19

第二章 實驗方法與材料 ---------------------------------------------------- 20
 2.1 實驗原理 ------------------------------------------------------------ 20
    2.1.1 重組與純株化(recombinant DNA and cloning) ---------------------- 20
    2.1.2 聚合酶連鎖反應(polymerase chain reaction) ---------------------- 21
    2.1.3 微矩陣基因晶片酵素呈色原理 ------------------------------------- 22
 2.2 實驗藥品 ------------------------------------------------------------ 24
 2.3 cDNA微矩陣基因晶片實驗藥品配置 -------------------------------------- 25
 2.4 實驗方法 ------------------------------------------------------------ 26
2.4.1 細胞培養 ----------------------------------------------------------- 26
    2.4.2 細胞之紫外線照射 ----------------------------------------------- 27
    2.4.3 細胞之信使核糖核酸(mRNA)抽取 ----------------------------------- 28
    2.4.4 cDNA微矩陣基因晶片 --------------------------------------------- 29
    2.4.5 資料處理 ------------------------------------------------------- 31
    2.4.6 統計分析 ------------------------------------------------------- 32
    2.4.7 反轉錄聚合酶連鎖反應(RT-PCR) ----------------------------------- 32
    2.4.8 重組xpc基因 ---------------------------------------------------- 34
    2.4.9 質體抽取 ------------------------------------------------------- 35
    2.4.10 Lipofectamine transfection ------------------------------------ 35
    2.4.11 MTT assay ----------------------------------------------------- 35

第三章 實驗結果與討論 ---------------------------------------------------- 37
 3.1 細胞受紫外線照射後之存活率 ------------------------------------------ 37
 3.2 核糖核酸(RNA)與信使核糖核酸(mRNA)之品質判定 ------------------------- 39
 3.3 細胞受紫外線照射後之基因表現 ---------------------------------------- 40
 3.4 微矩陣基因晶片雜交數據分析之原理 ------------------------------------ 41
 3.5 微矩陣基因晶片雜交數據比較 ------------------------------------------ 44   
 3.6 微矩陣基因晶片之t-test數據 ------------------------------------------ 50
 3.7反轉錄聚合酶連鎖反應(RT-PCR)驗證統計之結果 --------------------------- 57
 3.8 基因功能的分析 ------------------------------------------------------ 66
3.8.1 GADD153 ------------------------------------------------------------ 67 
3.8.2 GADD45A ------------------------------------------------------------ 68

第四章 結論 -------------------------------------------------------------- 82

參考文獻 ----------------------------------------------------------------- 84

自述 --------------------------------------------------------------------- 93



表目錄
表1-1 830個著色性乾皮症之臨床症狀觀察 ----------------------------------  9
表1-2 核酸切除修復之因子 ----------------------------------------------- 10
表1-3 卵巢癌細胞相對於正常卵巢細胞表現上升之基因及倍數 ----------------- 16
表1-4 卵巢癌細胞相對於正常卵巢細胞表現下降之基因及倍數 ----------------- 16
表2-1 本實驗所使用之細胞株 --------------------------------------------- 27
表2-2 千禧DNA晶片之基因種類與數目 -------------------------------------- 29
表2-3反轉錄聚合酶連鎖反應之引子 ---------------------------------------- 33
表3-1 Housekeeping genes ----------------------------------------------- 44
表3-2 Stress response genes與其所佔之因數荷量(factor loading) ---------- 46
表3-3 Stress response genes經PCA分析後所得因數之因數值 ----------------- 47
表3-4 Factor 1基因進行t-test分析後的基因表現數值 ----------------------- 51
表3-5 Factor 3基因進行t-test分析後的基因表現數值 ----------------------- 52 
表3-6 Factor 4基因進行t-test分析後的基因表現數值 ----------------------- 52
表3-7 Factor 1基因進行RT-PCR分析定量後的基因表現倍數 ------------------- 64
表3-8 Factor 3基因進行RT-PCR分析定量後的基因表現倍數 ------------------- 65
表3-9 Factor 4基因進行RT-PCR分析定量後的基因表現倍數 ------------------- 65
表3-10 β-actin基因進行RT-PCR分析定量後的基因表現倍數 ------------------- 65
表3-11 
(a) 修復功能正常細胞之GADD153基因表現之RT-PCR量化結果------------------- 78
(b) XPC亞型細胞之GADD153基因表現之RT-PCR量化結果 ----------------------- 78
(c) XP細胞之GADD153基因表現之RT-PCR量化結果 ---------------------------- 79
(d) CS細胞之GADD153基因表現之RT-PCR量化結果 ---------------------------- 79
表3-12 
(a) 修復功能正常細胞之GADD45A基因表現之RT-PCR量化結果------------------- 80
(b) XPC亞型細胞之GADD45A基因表現之RT-PCR量化結果 ----------------------- 80
(c) XP細胞之GADD45A基因表現之RT-PCR量化結果 ---------------------------- 81
(d) CS細胞之GADD45A基因表現之RT-PCR量化結果 ---------------------------- 81

圖目錄
圖1.1 (a)四種型式的含氮鹽基.(b)嘌呤與嘧啶間的氫鍵結合型式---------------  2
圖1.2 紫外線光譜 -------------------------------------------------------  3
圖1.3 環丁烷嘧啶雙體 ---------------------------------------------------  4
圖1.4 6-4嘧啶光產物  ---------------------------------------------------  4
圖1.5 整體核酸切除修復(NER)之步驟 --------------------------------------  8
圖1.6基因晶片點製機台 -------------------------------------------------- 11
圖1.7 (a)非接觸式點針, (b)接觸式點針 ----------------------------------- 12
圖1.8 (a) Cyanine-3-dUTP, (b) Cyanine-5-dUTP之分子式 ------------------- 13
圖1.9 hHR23A & B之氨基酸順序與XPC結合部位 ------------------------------ 18
圖1.10 本文研究架構 ---------------------------------------------------- 19
圖2.1 PCR之反應過程 ---------------------------------------------------- 21
圖2.2 Biotin-16-dUTP之分子式 ------------------------------------------- 23
圖2.3 酵素呈色法之機制 ------------------------------------------------- 23
圖2.4 細胞照射紫外線之流程 --------------------------------------------- 28
圖2.5 ScanAlyze 2計算訊號強度方式 -------------------------------------- 31
圖2.6 重組xpc基因至pcDNA3.1 B載體 -------------------------------------- 34     圖2.7 (a) MTT之分子式, (b) formazan之分子式 ---------------------------- 36
圖2.8 MTT與formazan之紫外線吸收光譜 ------------------------------------ 36
圖3.1 細胞受紫外線照射後之存活率曲線圖 --------------------------------- 38
圖3.2 核糖核酸之瓊膠電泳圖 --------------------------------------------- 39
圖3.3細胞之mRNA與微矩陣基因晶片雜交後呈色之結果 ------------------------ 40
圖3.4 基因表現趨勢圖 --------------------------------------------------- 48
圖3.5 Factor 1基因之t-test表現趨勢圖 ----------------------------------- 53
圖3.6 Factor 3基因之t-test表現趨勢圖 ----------------------------------- 55
圖3.7 Factor 4基因之t-test表現趨勢圖 ----------------------------------- 56
圖3.8用RT-PCR分析β-actin基因表現變化結果 ------------------------------- 57
圖3.9用RT-PCR分析factor 1中基因表現變化結果 
(a) c-Fos基因表現變化結果 ---------------------------------------------- 58
(b) c-Myc基因表現變化結果 ---------------------------------------------- 59
(c) GADD153基因表現變化結果 -------------------------------------------- 60
(d) GADD45A基因表現變化結果 -------------------------------------------- 61
圖3.10 用RT-PCR 分析factor 3中Jun B基因表現變化結果 -------------------- 62
圖3.11 用RT-PCR 分析factor 4中EGR 1基因表現變化結果 -------------------- 63
圖3.12 用RT-PCR 分析之GADD153基因表現變化結果 
(a) DNA修復功能正常細胞 ------------------------------------------------ 70
(b) XPC亞型細胞 -------------------------------------------------------- 71
(c) XP細胞 ------------------------------------------------------------- 72
(d) CS細胞 ------------------------------------------------------------- 73
圖3.13 用RT-PCR 分析之GADD45A基因表現變化結果 
(a) DNA修復功能正常細胞 ------------------------------------------------ 74
(b) XPC亞型細胞 -------------------------------------------------------- 75
(c) XP細胞 ------------------------------------------------------------- 76
(d) CS細胞 ------------------------------------------------------------- 77
                                    

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