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研究生:林美嫻
研究生(外文):Mei Hsien Lin
論文名稱:探討人類POLD1基因對前列腺癌細胞的調控及作用機制
論文名稱(外文):Understanding The Function And Regulation of The DNA Polymerase Catalytic Subunit Gene POLD1 in The Human Prostate Carcinoma Cells
指導教授:莊宏亨
指導教授(外文):H. H. Juang
學位類別:碩士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
論文頁數:120
中文關鍵詞:前列腺癌DNA聚合酶基因調控腫瘤標的訊息調控
外文關鍵詞:POLD1DNA replicationcell proliferationprostate cancergene regulation
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在真核細胞中,至少含有五種不同的DNA聚合酶,分別為polymerase α (pol α), polymerase β (pol β), polymerase γ (pol γ), polymerase δ (pol δ)以及polymerase ε (pol ε) 。這些不同的聚合酶在DNA的合成反應中,各自扮演著重要的角色。polymerase δ次單元的基因,又稱為POLD1基因,其蛋白質分子量為125 kDa。POLD1基因具有表現DNA聚合酶及3’到5’方向外核酸酶雙重活性的能力。於流式細胞儀分析及細胞生長實驗中,發現knock-down POLD1基因能夠抑制前列腺癌細胞株PC-3細胞生長,使細胞週期停滯於S-phase。投予doxorubicin於前列腺癌細胞株LNCaP或暫時性大量表現p53於PC-3細胞中,證實p53會藉由POLD1啟動子上的p53 consensus sequence,抑制POLD1的基因表現。藉由RT-PCR、西方點墨法及暫時性基因報導法實驗,也發現雄性素致效劑R1881作用於LNCaP細胞株中,會透過間接方式、負調控POLD1基因的表現。POLD1基因也會受到NFκB因子的影響,但在雄性素敏感性LNCaP細胞及雄性素不敏感性細胞PC-3間,具有不同的反應。此外,低氧環境也會促進PC-3細胞株生長,此反應可能與誘導POLD1基因表現相關。大量表現PDEF於DU145細胞株,也證實會使得POLD1基因的表現增加,而NKX3.1及NDRG1則會抑制POLD1基因的活性於PC-3細胞。藉由本論文之研究成果,證實了於前列腺癌細胞中,POLD1基因是一種重要的調控因子,會影響癌細胞的生長。且POLD1基因的表現會受到雄性素、p53、NFκB、HIF-1α、PDEF、NKX3.1、NDRG1等藥物或轉錄因子的影響。
In Eukaryotes there are five DNA polymerase including alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis. The 125 kDa subunit (POLD1) of DNA polymerase delta contains the polymerase active site and the active site for the 3’-5’-exonuclease activity. Results from 3H-thymidine incorporation assay and flow cytometric analysis reveal that knock-down POLD1 gene expression attenuates cell proliferation and arrest cell cycle at S phase in human prostate carcinoma PC-3 cells. Using doxorubicin-treated LNCaP cells and p53-overexpresssion PC-3 cells, our study demonstrates that p53 blocks POLD1 gene expression through a consensus p53 response element. Results from reporter assays, immunoblot assays and RT-PCR indicate that R1881, an androgen analog, indirectly blocks the gene expression of POLD1 in LNCaP cells. Gene expression of POLD1 is also modulated by NFκB; however, androgen-sensitivity and androgen-insensitivity prostate carcinoma cells have contrary results. Hypoxia induce cell proliferation may due to the upregulation of POLD1 gene expression in PC-3 cells which is determined by 3H-thymidine incorporation, immunoblot and reporter assays. Stably-overexpression of prostatic specific NKX3.1 homeobox gene or NDRG1 gene in PC-3 cells attenuates cell proliferation and blocks gene expression of POLD1. Forced-overexpression of PDEF (prostate-derived Ets factor) in DU145 cells enhances cell proliferation and upregulates gene expression of POLD1. This study provides the first evidence of the biological mechanism of human POLD1 gene which is important modulator of cell proliferation in the human prostate carcinoma cells; moreover, the gene expression of POLD1 is regulated by androgen, p53, NFκB, HIF-1α, NKX3.1, NDRG1 and PDEF.
目錄
誌謝.............................................................................................................v
縮寫對照表...............................................................................................vi
中文摘要.................................................................................................viii
英文摘要...................................................................................................ix
目錄.............................................................................................................x
圖表目錄.................................................................................................xiv
壹、 緒論.......................................................................................1
一、POLA之結構、功能與基因調控之探討...............................2
二、POLD1之結構、功能與基因調控之探討.............................5
三、POLE之結構、功能與基因調控之探討................................7
四、p53之功能與機制.....................................................................9
五、Nuclear Factor-kappa B (NFκB) 之功能與機制..................11
六、Hypoxia inducible factor 1α (HIF-1α) 之功能與機制.........14
七、Prostate-derived Ets factor (PDEF) 之功能與機制.............17
八、NKX3.1之功能與機制............................................................19
九、NDRG1之功能與機制............................................................23
貳、 研究假說與目的..................................................................26
一、探討POLD1基因於前列腺癌細胞株的功能.......................27
二、探討轉錄因子與藥物對POLD1基因的調控.......................27
參、 實驗材料與方法..................................................................28
一、細胞培養和化學藥劑...............................................................29
二、蛋白質萃取及濃度測量...........................................................30
三、西方點墨法 (Immunoblot analysis)......................................31
四、RNA 萃取................................................................................31
五、反轉錄合成反應 (Reverse transcription for synthesis of
cDNA).......................................................................................33
六、聚合酶連鎖反應 (polymerase chain reaction).....................34
七、建構基因載體...........................................................................35
(1) 建構POLD1基因報導載體.............................................35
(2) 建構POLD1基因載體.....................................................36
(3) 建構POLD1 siRNA載體.................................................36
(4) 建構PDEF基因載體........................................................37
(5) 建構NKX3.1基因載體.....................................................37
(6) 建構NFκB基因報導載體................................................38
(7) 建構IL-6基因報導載體..................................................38
(8) 建構IκBαm基因載體......................................................39
(9) 建構NIK基因載體..........................................................39
八、暫時性基因報導法(Luciferase Assay)...................................39
九、建立穩定性表達特定基因細胞株(Stable transfection)........40
十、Cell Proliferation Assay..........................................................41
十一、MTS assay............................................................................41
十二、DNA incorporation assay....................................................43
十三、Cell cycle analysis................................................................43
十四、統計分析...............................................................................45
肆、結果......................................................................................46
一、POLD1於前列腺癌細胞中的表現........................................47
二、抑制POLD1基因表現對PC-3細胞生長的影響..................48
三、觀察過度表達POLD1基因對前列腺癌的影響....................48
四、p53對POLA、POLD1及POLE基因的調控....................49
五、雄性素對POLA、POLD1及POLE基因的調控...............50
六、NFκB對POLA、POLD1及POLE基因的調控................52
七、Hypoxia對POLA、POLD1、POLE基因的調控..............54
八、PDEF對POLA、POLD1、POLE基因的調控..................55
九、NKX3.1對POLA、POLD1、POLE基因的調控...............55
十、NDRG1對POLA、POLD1、POLE基因的調控...............56
伍、討論......................................................................................57
一、POLD1基因影響前列腺癌細胞之生長................................58
二、p53透過啟動子上的response element抑制POLD1基因的
. 表現...........................................................................................59
三、雄性素透過間接方式抑制POLD1基因的表現...................60
四、NFκB對POLD1基因的調控受到前列腺癌細胞對雄性素敏
感性的影響...............................................................................62
五、Hypoxia可能藉由促進POLD1基因的表現加速PC-3細胞
生長...........................................................................................64
六、PDEF促進DU145細胞生長及誘導POLD1基因表..........64
七、NKX3.1抑制PC-3細胞生長和POLD1基因表現..............65
八、NDRG1抑制POLA、POLD1、POLE基因的表現...........65
陸、圖與圖說..............................................................................67
柒、附錄.......................................................................................80
捌、參考文獻...............................................................................89
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