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研究生:阮子亘
研究生(外文):Tzu-Shiuan
論文名稱:探討結腸直腸癌中Daxx對P53所調控腫瘤抑制之影響
論文名稱(外文):Effect of Daxx on the P53-mediated tumor suppression in colorectal cancer
指導教授:曾淑玲曾淑玲引用關係
指導教授(外文):Shu-Ling Tzeng
學位類別:碩士
校院名稱:中山醫學大學
系所名稱: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:2010
畢業學年度:98
語文別:中文
論文頁數:72
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在大多數的結腸直腸癌中可發現其Wnt signaling pathway有持續活化的情形,研究證實Daxx可降低Transcription factor 4(Tcf4)的DNA結合活性,進而抑制Wnt signaling pathway的活化,並且發現在結腸癌組織中Daxx蛋白表現有減少的情形,可知Daxx在結腸直腸癌的致癌過程扮演很重要的角色,P53腫瘤抑制基因是一個轉錄因子,P53會轉錄活化下游基因,阻斷細胞週期而造成G1休止,Daxx也已知是一個轉錄調節者,有多篇文獻已證實Daxx會與P53結合,因此本研究目的為探討結腸直腸癌中Daxx對P53所調控腫瘤抑制之影響。
首先證實在Daxx 蛋白靜默表現的結腸癌細胞中,其P53表現明顯的減少,使用轉殖方式將Daxx表現量增加,其P53訊號表現也會隨著增加。進行細胞增生速率的分析,發現在Daxx 蛋白靜默表現的結腸癌細胞中,細胞的生長速率明顯增快,Daxx或P53的回復表現會趨緩Daxx 蛋白靜默表現的結腸癌細胞的生長速率,結果顯示在結腸癌細胞中Daxx 蛋白會正向調控P53蛋白的表現。結腸癌細胞給予UV照射、或處理Etoposide(ETO)、5-fluorouracil (5-FU)、Mitomycin C(MMC) 24、48小時都會活化P53的表現, Daxx蛋白表現的靜默有較高的敏感度,並且增強P53誘發的細胞凋亡。初步分析130組的配對臨床檢體發現有72(55%)的檢體其Daxx表現減少,伴隨著其P53訊號表現也呈現一致性的減弱。研究結果顯示在結腸直腸癌中,其Daxx的表現減少確實會抑制P53的表現,而Daxx蛋白表現的靜默會使結腸癌細胞對DNA所誘發的細胞凋亡較敏感,Daxx具有潛力可發展為未來結腸直腸癌的抗癌治療上的新標的。


Abstract
Constitutive activation of the canonical Wnt signaling pathway is observed in a majority of colon cancers. Daxx reduces activation of the Wnt signaling. Reduction of Daxx protein expression has been observed in colon adenocarcinoma tissue compared with normal colon tissue. Daxx may play an important role in carcinogenesis of colon cancer. The tumor suppressor gene P53 plays signicant roles in growth arrest, DNA repair and apoptosis, by acting as a transcription factor to modulate the expression of various genes. Recently researchs have suggest that Daxx interacts with P53. In this present study, we want to examine effect of Daxx on the P53-mediated tumor suppression in colorectal cancer. In Daxx knock down stable cells, decreasing of Daxx resulted in P53 reduction, and transient transfection with Daxx could rescue this reduction. Following Proliferation rate assay was measured to demonstrat Daxx knockdown cell significantly increase growth rate compared with control vector transfected cells, Daxx and P53 overexpresssion can retard the growth rate of Daxx knock down cells. These results show that Daxx can upregulation expression of P53 in CRC cells. Hct116 cells were treated with UV irradiation for 30min,Etoposide (ETO), 5-fluorouracil (5-FU), Mitomycin C (MMC) for 24 and 48hr to induced P53 and apoptosis. Downregulation of Daxx by shRNA strongly potentiated P53-dependent apoptosis in HCT116. With clinical 130 paired colon adenocarcinoma tissues were comparison in protein detection by western blotting. The evidences indicated the decreased Daxx accompany P53 reduction in almost halt of paired tissues(55%,72 /130).These results may indicate that reduction of Daxx can repress P53 expressing in CRC, and Daxx silencing sensitizes Hct116 cells to DNA damage induced apoptosis , Daxx may be a potential novel target for future anticancer therapeutic development in colon cancer.


緒論
一、 結腸直腸癌 1
二、 Daxx相關研究 4
三、 P53相關研究 7
四、 P53和apoptosis相關研究 9
五、 P53和抗藥性相關研究 11
研究目的 12
實驗方法材料
一、 細胞培養 13
二、 細胞週期分析 14
三、 細胞凋亡分析 15
四、 組織蛋白質萃取 16
五、 蛋白質定量 17
六、 西方點墨法 17
七、 細胞轉染 19
八、 Luciferase assay 20
九、 細胞增生速率測定 21
實驗結果
一、 在結腸癌細胞中Daxx蛋白的減少會抑制P53蛋白的表現 23
二、 在D3-1細胞增加Daxx蛋白的表現量可提高其P53蛋白的表現 23
三、 Daxx蛋白的表現不影響P53轉錄活性功能 24
四、 Daxx和P53的蛋白表現減少會增快Hct116細胞株的生長速率 24
五、 Daxx蛋白的減少會加快Hct116細胞株的細胞週期 25
六、 Daxx蛋白的減少會增加Hct116細胞株對DNA損傷的敏感性 25
七、 結腸直腸癌組織中Daxx蛋白和P53蛋白表現為正相關 28
討論
一、 在結腸癌細胞中Daxx蛋白會正向調控P53蛋白的表現 30
二、 Daxx和P53的蛋白表現減少會加速Hct116細胞株的增
生速率和細胞週期 30
三、 Daxx蛋白的減少會增加Hct116細胞株對DNA損傷的敏感性 32
四、 結腸直腸癌組織中Daxx蛋白和P53蛋白表現為正相關 33
結論 35
圖表
Table 1、結腸直腸癌組織其Daxx和P53蛋白表現的相關性 57
Table 2、Daxx蛋白表現與結腸直腸癌病理特徵的相關性 58
Table3、P53蛋白表現與結腸直腸癌病理特徵的相關性 59
Fig.1、D3-1細胞中其P53的蛋白表現明顯減少 36
Fig.2、在D3-1細胞株中Daxx不同片段對P53的蛋白的影響 38
Fig.3、Daxx蛋白的表現不影響P53轉錄活性功能 40
Fig.4、Daxx和p53的表現減少會增快Hct116細胞的生長速率 41
Fig.5、Daxx蛋白的減少會加快Hct116細胞株的細胞週期 43
Fig.6、Daxx蛋白的減少會增加Hct116細胞株對UV照射的敏感性 46
Fig.7、Daxx蛋白的減少會增加Hct116細胞株對Mitomycin C處理
的敏感性 48
Fig.8、Daxx蛋白的減少會增加Hct116細胞株對5-FU的敏感性 51
Fig.9、Daxx蛋白的減少會增加Hct116細胞株對Etoposide 處理的
敏感性 54
Fig.10、JL-1、D3-1細胞對UV以及不同的藥物處理的敏感性 56
Fig.11、結腸直腸癌組織中Daxx蛋白和P53蛋白表現的相關性 60
參考文獻 62
口試問答紀錄 71


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