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研究生:周士翔
研究生(外文):Shih-Hsiang Zhou
論文名稱:肝腫瘤細胞中轉錄因子Sp1及C/EBPα調控DDX3表現之機轉
論文名稱(外文):Regulation of DDX3 Expression by Sp1 and C/EBPα in Hepatocellular Carcinoma Cells
指導教授:吳妍華
指導教授(外文):Yan-Hwa Wu Lee
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:88
中文關鍵詞:DDX3Sp1C/EBPα肝腫瘤細胞
外文關鍵詞:DDX3Sp1C/EBPαHCC
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肝癌是全球名列第五發生率的癌症,其中肝細胞癌(hepatocellular carcinomas;HCC)占了80%左右。在HCC中,DDX3的蛋白質及mRNA表現量是下降的趨勢;本實驗室先前研究發現DDX3會與Sp1發生蛋白質交互作用促進p21之表現,在HCC中,DDX3表現量下降,造成p21表現量下降,進而造成肝癌細胞不斷生長。但是對於DDX3基因之調控現今並不清楚,所以想要針對DDX3表現之調控機轉進行研究。首先將臨床HCC病人檢體萃取出genomic DNA,將DDX3啟動子進行定序,定序結果發現,HCC病人的DDX3 啟動子之突變位置的再現性很低,不足以代表是因為DDX3啟動子發生DNA突變而造成HCC中DDX3表現量下降。在HCC中DDX3表現量下降可能是轉錄因子不正常表現所造成,所以先找尋出影響DDX3表現之轉錄因子。本實驗室先前研究發現DDX3啟動子的-180至-160區域對DDX3啟動子活性相當地重要。兩個Sp1 recognition site [Sp1 (-163)及Sp1 (-102)]和一個C/EBPα recognition site [C/EBPα(-139)]對DDX3 啟動子活性是相當重要的。利用real-time PCR進一步研究Sp1及C/EBPα這兩個轉錄因子在臨床檢體中之表現量,發現DDX3 mRNA表現與Sp1 mRNA表現有關聯性。在Luciferase reporter assay證實Sp1和C/EBPα對DDX3啟動子活性相當地重要,也發現Sp1與C/EBPα以協同作用方式來調控DDX3啟動子活性。在Sp1與C/EBPα的共同轉染的研究發現DDX3蛋白質表現有減緩之趨勢。為了瞭解DDX3是否具自我調控,轉染DDX3 表現質體至HuH-7 cells後,進行Luciferase reporter assay發現DDX3啟動子活性隨著DDX3表現量增加而降低,推測DDX3具有自我調控。而此自我調控之調控機轉可能是DDX3與Sp1結合之後,Sp1失去其原本的轉錄活化能力。經上述之內容所得之結論為Sp1與C/EBPα以協同作用方式調控DDX3之表現及DDX3與Sp1結合來達到DDX3自我調控之調節。
Primary liver cancer is the fifth most common cancer worldwide. Hepatocellular carcinoma is 80% of primary liver cancer. Our previous data showed that the protein and mRNA levels of DDX3 are reduced in HCC. The protein-protein interaction between DDX3 and Sp1 promotes p21 expression and the reduction of DDX3 expression led to the decreased expression of p21. But the regulation mechanisms of DDX3 expression remain undefined. To investigate the mechanism of DDX3 expression regulation in HCC, the nucleotide sequences of 1.5 kb DDX3 promoter fragments were analyzed by sequencing. These mutation sites were not reproducible in the DDX3 promoter fragment. The low reproducibility indicated that downregulation of DDX3 in HCC specimens cannot be due to DNA mutation of DDX3 promoter fragment. Our previous data showed that the -180 ~ -160 region in the DDX3 promoter region (translation start site as +1) is important for DDX3 promoter activity. Mutational analysis indicated that two Sp1 recognition sites, Sp1 (-163) and Sp1 (-102), and one C/EBPα(-139) recognition site in DDX3 upstream regulatory region are critical for DDX3 promoter activity. In this study, by using real-time RT-PCR, we found a correlation between the profile of DDX3 mRNA and Sp1 mRNA in HCC specimens. Sp1 and C/EBPα are required for DDX3 promoter activity and a synergistic regulation of DDX3 promoter activity by these two transcription factors are found. However, the DDX3 protein level is reduced by co-transfection of Sp1 and C/EBPα expression constructs. To clarify whether DDX3 expression is autoregulated, we further confirm this result by overexpression of DDX3 and Sp1 in a DDX3 promoter-driven reporter assay. DDX3 may have autoregulation ability in its promoter and this autoregulation could be due to DDX3 binding with Sp1 that lead to loss of Sp1 transactivation ability. All together, our results suggest that the reduced DDX3 expression in HCC specimen is not caused by DNA mutation of DDX3 promoter region. DDX3 expression is regulated by the synergism between C/EBPα and Sp1 transcription factors. Interestingly, DDX3 expression may be modulated by DDX3 autoregulation through the protein-protein interaction between DDX3 and Sp1.
目錄……………………………………………………………1

圖表目錄………………………………………………………………………………4
中文摘要………………………………………………………………………………5
Abstract ………………………………………………………………………………6
縮寫表…………………………………………………………………………………8
壹、 緒論 …………………………………………………………………………12
一、肝癌之流行病學………………………………………………………………12
(一)盛行區域…………………………………………………………………12
(二)性別………………………………………………………………………13
(三)年齡………………………………………………………………………13
(四)種族………………………………………………………………………13
(五)危險因子…………………………………………………………………13
(1)環境因子………………………………………………………………13
(a)酗酒…………………………………………………………………14
(b)黃麴毒素(Aflatoxin B1, AFB1)………………………………………14
(c)菸草…………………………………………………………………14
(2)代謝性疾病(Hemochromatosis)……………………………………14
(3)血鐵沉著症…………………………………………………………14
(4)病毒感染………………………………………………………………15
(a) B型肝炎病毒(Hepatitis B virus, HBV)………………………………15
(b) C型肝炎病毒(Hepatitis C virus, HCV)………………………………15
(六)基因的活化與HCC之關係………………………………………………16
(1)Oncogene………………………………………………………………16
(a) β-catenin……………………………………………………………16
(b) Frizzled-7 receptor (FZD7)……………………………………………16
(2) Growth factor…………………………………………………………16
(a) TGF-α…………………………………………………………………16
(b) IGF-II…………………………………………………………………17
(3) Telomerase enzyme……………………………………………………17
(七)基因的失活與HCC之關係………………………………………………17
腫瘤抑制因子(Tumor suppressor)……………………………………17
(1) p53……………………………………………………………………18
(2) E-cadherin……………………………………………………………18
二、RNA helicase DDX3……………………………………………………………18
(一)DDX3與RNA metabolism…………………………………………………19
(二)DDX3與癌症………………………………………………………………20
三、Specific factor 1 (Sp1)…………………………………………………………21
(一)Sp家族簡介………………………………………………………………21
(二)Sp1簡介……………………………………………………………………22
(三)Sp1之轉譯後修飾(post-translational modification)………………………22
(四)Sp1與癌症…………………………………………………………………23
四、CCATT/enhancer binding protein alpha (C/EBPα)……………………………24
(一)C/EBP家族簡介……………………………………………………………24
(二)C/EBPα簡介………………………………………………………………24
(三)C/EBPα之轉譯後修飾(post-translational modification)…………………25
(四)C/EBPα與癌症……………………………………………………………26
貳、研究動機與策略………………………………………………………………27
参、實驗材料與方法………………………………………………………………28
一、實驗材料………………………………………………………………………28
1、菌株…………………………………………………………………………28
大腸桿菌(Escherichia coli)…………………………………………………28
2、細胞株………………………………………………………………………28
3、培養基與培養液……………………………………………………………28
4、質體…………………………………………………………………………29
A、非本論文所構築之質體…………………………………………………29
B、商業化之質體……………………………………………………………30
5、溶液…………………………………………………………………………30
6、化學藥品……………………………………………………………………33
7、酵素…………………………………………………………………………33
8、抗體…………………………………………………………………………33
9、引子合成……………………………………………………………………33
10、臨床人類肝癌組織…………………………………………………………33
二、實驗方法………………………………………………………………………34
1、大腸桿菌質體之轉型 (Transformation)……………………………………34
2、大腸桿菌質體之抽取………………………………………………………34
A、小量製備(Mini-preparation)……………………………………………34
B、大量製備(Maxi preparation)……………………………………………34
3、細胞培養……………………………………………………………………35
4、A-tailing procedure for blunt-ended PCR fragments………………………35
5、接合作用 (Ligation)…………………………………………………………36
6、聚合酶鏈鎖反應 (Polymerase chain reaction, PCR)………………………36
7、藍白試驗(Blue-White test)…………………………………………………37
8、Genejuice transfection (Roche)……………………………………………37
9、Denatured SDS-聚丙醯胺凝膠電泳 (SDS dodecyl sulfate-polyacrylamide gel
electrophoresis, SDS-PAGE)…………………………………………………37
10、西方點墨法 (Western blot)………………………………………………38
11、即時定量PCR (real-time PCR)……………………………………………38
12、Luciferase reporter assay…………………………………………………39
肆、實驗結果………………………………………………………………………40
一、DDX3表現量下降與DDX3 promoter發生DNA突變無關…………………40
二、HCC臨床檢體中Sp1及C/EBPα mRNA表現量趨勢………………………41
三、Sp1及C/EBPα調控DDX3啟動子活性……………………………………42
四、Sp1與C/EBPα以協同作用方式調控DDX3 啟動子活性…………………44
五、Sp1與C/EBPα對DDX3蛋白質表現之影響………………………………44
六、DDX3具有自我調控之能力…………………………………………………45
七、DDX3自我調控受DDX3與Sp1所調節……………………………………45
伍、討論……………………………………………………………………………47
一、HCC中降低的DDX3表現與DDX3啟動子DNA突變之關係……………47
二、HCC中Sp1及C/EBPα mRNA表現量之相關性……………………………47
三、DDX3啟動子上重要的轉錄因子結合位……………………………………48
四、Sp1與C/EBPα調節DDX3表現之機轉……………………………………49
五、DDX3自我調控之機轉……………………………………………………50
陸、參考文獻………………………………………………………………………52
柒、Tables and Figures………………………………………………………………67
捌、附錄……………………………………………………………………………86
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