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研究生:楊盈芝
研究生(外文):Ying-Chihi
論文名稱:藉由增加TNF receptor-1表現Genistein促進 trichostatin A 抑制 A549細胞生長之效果
論文名稱(外文):Genistein enhanced the effects of trichostatin A on inhibition of A549 cells growth by increasing the expression of TNF receptor-1.
指導教授:葉姝蘭
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:營養學研究所
學門:醫藥衛生學門
學類:營養學類
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:70
相關次數:
  • 被引用被引用:2
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我們先前的研究發現,genistein 促進trichostatin A (TSA)誘發
肺癌細胞A549 凋亡,但genistein 造成此結果的真正機制並不清楚,我們由microarray 分析結果發現可能與genistein 增加death receptor,tumor necrosis factor receptor-1 (TNFR-1) 的表現量有關,因此本研究主要目的是驗證genistein 增加TSA 抑制癌細胞生長是否透過調節TNFR-1,進而引起下游signaling cascade,而增加肺癌細胞A549 的凋亡。A549 細胞以TSA (50 ng) 和genistein (5、10μM) 單獨或合併處理一段時間後發現,如預期的, 5 和10 μM genistein 可顯著增加TSA 誘發細胞生長停滯,並具劑量效應,同時TSA 合併genistein 處理6 及12 小時,TNFR-1 的mRNA 和蛋白質的表現量亦顯著較TSA單獨處理組高,合併處理後,與TSA 單獨組相比,亦會增加caspase-10及caspase-3 mRNA 表現及活性,而caspase-8 mRNA 表現及活性則不受影響。我們利用轉染siRNA 的方式抑制A549 細胞內TNFR-1 的表現,結果發現genistein 促進TSA 抑制細胞生長及增加caspase-3 的活性的效應都被抑制。綜合以上結果證明,增加細胞凋亡外在途徑,亦即TNFR-1 表現,在genistein 促進TSA 誘發肺癌細胞A549 凋亡的機制上應扮演重要角色。


Our previous study has shown that genistein enhance the apoptosis in A549 lung cancer cells induced by trichostatin Our previous study has shown that genistein enhance the apoptosis in A549 lung cancer cells induced by trichostatin A (TSA). The precise mechanisms underlying such an effect of genistein, however, is unclear.From microarray assay, we found that the increase of death receptor,tumor necrosis factor receptor-1 (TNFR-1), induced by genistein may
play an important role. Thus, in the present study, we investigated whether genistein enhance the anti-cancer effect of TSA through up-regulation of TNFR-1 death receptor signaling. We incubated A549 cells with TSA (50 ng/mL) alone or in combination with genistein for a
period of time. As expected, 5 and 10μM of genistein significantly increased the cell growth arrest induced by TSA in a time- and dose-dependent manner. Incubation of TSA in combination with genistein, TNFR-1 mRNA and protein expression were significantly increased at 6 and 12 hrs, respectively, as compared with that of TSA alone group. The combinative treatment also increased the mRNA expression and the activity of TSA-induced caspase-10, but not caspase-8,in A549 cells compared with TSA alone group. Furthermore, the combinative treatment increased the mRNA expression and the activity of TSA-induced caspase-3. Using transfection of siRNA to silence the expression of TNFR-1, we found that the enhancing effects of genistein on TSA-induced apoptosis, the caspase-3 activity in A549 cells were
suppressed. These data demonstrated that the up-regulation of TNFR-1 death receptor pathway play an important role, at least in part, in the enhancing effect of genistein on TSA-induced apoptosis in A549 cells.

縮寫表..................................................Ⅰ
中文摘要................................................Ⅱ
英文摘要................................................Ⅲ
一、前言
1.緒論...................................................1
2.文獻探討...............................................3
2.1異黃酮 ( Isoflavones).............................................3
2.2組蛋白去乙醯化酶抑制劑
( Histone deacetylases inhibitors-HDIs ).................6
2.3 藥物-phytochemicals及phytochemicals之間的交互作用..9
2.4腫瘤壞死因子受體-1
(Tumor necrosis factor receptor-TNFR-1)..................11
2.5 細胞程式性凋亡(Apoptosis)..........................13
2.6 研究目標.......................................................15
2.7 實驗架構...........................................16

二、材料與方法...........................................18
1.材料...................................................18
(1)儀器.......................................................18
(2)藥品................................................19
2.方法...................................................21
2.1細胞株來源及培養條件.......................................................21
2.2藥物培養.......................................................21
2.3細胞生長分析........................................22
2.4 RT-PCR (Reverse Transcriptase PCR) 分析基因表現-TNFR-1、caspase-8、caspase-10、caspase3.......................23
2.5西方墨點法 (Western blotting assay) -TNFR1.........27
2.6 Caspase-3、caspase-8、caspase-10活性測試...........31
2.7 siRNA Transfection (轉染TNFR-1 siRNA)..............33
2.8統計方法............................................34

三、結果與討論...........................................35
1.結果...................................................35
圖一. TSA單獨或合併不同濃度genistein對A549細胞生長影響...39
圖二. TSA、genistein單獨或合併其A549細胞TNFR-1 mRNA
表現量..............................................40
圖三. TSA、genistein單獨或合併其A549細胞TNFR-1 蛋白質
表現量..............................................41
圖四. TSA、genistein單獨或合併其A549細胞caspase-10 mRNA
表現量..............................................43
圖五. TSA、genistein單獨或合併其A549細胞caspase-8 mRNA
表現量..............................................44
圖六. TSA、genistein單獨或合併其A549細胞caspase-3 mRNA
表現量..............................................45
圖七. TSA合併不同濃度genistein對A549細胞caspase-3活性之影
響..................................................46
圖八. TSA合併不同濃度genistein對A549細胞caspase-8活性之影
響..................................................47
圖九. TSA合併不同濃度genistein對A549細胞caspase-10活性之影
響..................................................48
圖八. 轉染TNFR-1 siRNA後以TSA和不同濃度genistein單獨或合
併處理其A549細胞TNFR-1 mRNA表現量...................49
圖十一. 轉染TNFR-1 siRNA後以TSA和不同濃度genistein單獨或
合併處理對A549細胞生長影響........................50
圖十二. 轉染TNFR-1 siRNA後以TSA和不同濃度genistein單獨或
合併處理對A549細胞caspase-3活性之影響.............51
2.討論...................................................52

四.結論..................................................56
五.參考文獻..............................................57

附錄.....................................................66


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