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研究生:劉惠菁
研究生(外文):Hui-Ching Liu
論文名稱:探討以Quercetin及Luteolin對尼古丁誘導乳癌細胞株(MDAMB-231)增生的影響
論文名稱(外文):Effects of Quercetin and Luteolin on the Nicotine-induced Proliferation in Breast Cancer Cell Line ( MDA MB – 231 )
指導教授:何元順
指導教授(外文):Yuan-Soon Ho
學位類別:碩士
校院名稱:臺北醫學大學
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:2008
畢業學年度:96
語文別:中文
論文頁數:96
中文關鍵詞:尼古丁槲黃素木犀草素乳癌尼古丁受體 α9乳癌細胞株MDA MB-231
外文關鍵詞:nicotinequercetinluteolinbreast cancernAchR α9MDA MB-231
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中文摘要
( Abstract in Chinese )

許多文獻指出吸煙是引發肺癌的重要因子之一。在本實驗室之前的研究發現尼古丁受體 α9在尼古丁所誘發的乳癌中可能扮演著重要的角色。本研究主要目的是探討乳癌、尼古丁、以及天然化合物之間的關連性。MDA MB-231乳癌細胞株是雌性激素接受體陰性。而純化天然化合物 Quercetin 及 Luteolin 存在於一般日常生活常食用的蔬菜水果中,可抑制癌症細胞生長及許多訊息傳遞路徑的蛋白質表現。因此在本實驗中欲觀察在MDA MB-231給予Quercetin 及 Luteolin後是否能抑制尼古丁所誘發的尼古丁受體 α9表現量增加。
在MDA MB-231細胞株中, Nicotine隨著劑量增加會促使其增生,並使得其nAchR α9 mRNA及蛋白質表現量增加。而Nicotine影響nAchR α9 mRNA的表現會較蛋白質表現時間短。在MTT assay,或是RT-PCR及Western blot的實驗中,合併使用天然化合物 Quercetin 及 Luteolin,MDA MB-231細胞株的生長、nAchR α9 mRNA及蛋白質表現量均較單獨使用抑制效果為佳,儘管加入Nicotine也是如此。而在訊息傳遞方面,合併使用效果也較單獨使用更可以抑制Nicotine引起與PI3K/Akt傳遞路徑、MAPK傳遞路徑相關的蛋白質表現量。另外在細胞週期方面,Quercetin 及 Luteolin 能抑制細胞週期G1/S的調控蛋白cyclin D1的表現量,單獨使用或合併使用都有抑制效果,但兩者差別並不明顯。
藉由 Luciferase assay 實驗中發現 Quercetin 及 Luteolin 可抑制因為Nicotine 所誘導的nAchR α9 promoter活性。而模擬活體實驗的Soft agar assay中也可以觀察到 Quercetin 及 Luteolin 在單獨或混合使用皆可抑制MDA MB-231細胞株形成colony的能力。
Abstract
(Abstract in English)

Previous studies showed that tobacco-smoking is a well understanding carcinogenic factor that promotes the lung cancer formation. Previous reports had demonstrated that nicotine receptor α9 might play an important role in nicotine-induced breast cancer. The purpose of this study will figure out the correlation of breast cancer, nicotine, and natural compounds. MDA MB-231 is estrogen receptor negative breast cancer cell line. Quercetin and Luteolin are purified from natural fruits and vegetables. Both of them can suppress cancer cell growth and inhibit protein expression of signaling pathways. In this study, after adding Quercetin or/and Luteolin in MDA MB-231, I further investigated whether these compounds were involved in the inhibition of the over expression of nicotine-induced nicotine receptors.
In MDA MB-231 cell line, nicotine can induce cell growth, and expression of nAchR α9 mRNA and protein. Nicotine influences the mRNA level of nAchR α9 faster than the protein level. In MTT assay, RT-PCR and Western blot assay, the data showed that Quercetin or/and Luteolin can suppress cell growth, mRNA and protein expression of nAChR α9, with or without nicotine. In signal transduction, Quercetin or/and Luteolin can inhibit the protein expression of nicotine-induced PI3K/Akt and MAPK pathway, but inhibition of combination group is not significantly. Quercetin or/and Luteolin also can inhibit Cyclin D1 in cell cycle proteins, but inhibition of combination group is not significantly.
In Luciferase assay, Quercetin and Luteolin could inhibit nAchR α9 promoter activity through Nicotine induction. Soft agar assay showed that Quercetin or/and Luteolin also could supperess the colony formulation of MDA MB-231.
目錄 ( Contents )
頁數
中文摘要 ( Abstract in Chinese ) I
英文摘要 ( Abstract in English ) III
目 錄 ( Contents ) V
縮寫表 ( Abbreviations ) XI

第一章 緒論 ( Introduction ) …………………………………... 1
前言 ………………………………………………………….. 2
一、 乳癌與吸菸的關係 …………………………………5
二、 Nicotine & Nicotine acetylcholine receptors ( nAchRs)的介紹 ……………………………………………………6
三、 Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway介紹 …………………………………………………. ..9
四、 Mitogen-activated protein kinases (MAPK) signaling pathways ……………………………………………. .11
五、 細胞週期與細胞凋亡 ………………………………..14
六、 Quercetin and Luteolin的介紹 .…………………… .15

第二章 實驗材料與方法 ( Materials and Methods ) ………… ...20
一、 實驗材料 ……………………………………………. 21
1、 藥品試劑 ……….…………….………………….21
2、 常用溶液 ……….………………………….…….25
3、 常用儀器 ……….………………………….…… 26
二、 實驗方法 ……….…………………………….… .28
1、 細胞培養 Cell culture …………………….……. 28
2、 細胞存活率分析MTT cell viability assay ………. 29
3、 反轉錄-聚合酶連鎖反應Reverse transcriptase-Polymerase Chain Reaction ………. ..30
4、 西方墨點法 Western blotting assay ……….…. 33
5、 連續刪除片段生物冷光活性分析Serial deletion luciferase assay …………………………….… 37
6、 Soft agar assay ( Colony Formation Assay ) …….… 41

第三章 實驗結果 ( Results ) ……………………………………… 43
一、 Nicotine隨著劑量增加對於使乳癌細胞MDA MB-231生長的影響 …………………………………… .44
二、 Luteolin 及Quercetin各別或兩者混合使用對於Nicotine 誘發MDA MB-231細胞培養三天生長的影響 ……………………………………………..… .44
三、 比較Luteolin 及Quercetin各別或兩者混合使用對於抑制Nicotine誘發MDA MB-231細胞生長的影響 ……………………………………………… 45
四、 Nicotine作用於MDA MB-231乳癌細胞中能引起nAchR α9 mRNA最佳的反應劑量 .………………..…....…46
五、 10 μM Nicotine影響MDA MB- 231 nAchR α9 mRNA表現的最佳作用時間 ………………………… 46
六、 單獨使用Quercetin 或 Luteolin或兩者合併使用對於MDA MB-231乳癌細胞中的nAchR α9 mRNA的表現影響 …………………………….………….… 47
七、 單獨或合併使用Luteolin與Quercetin pretream之後,再加入10 μM Nicotine, 對於MDA MB-231 nAchR α9 mRNA表現的抑制情形 .….…………….…… .48
八、 Nicotine隨著劑量增加至10μM時對於MDA MB-231 nAchR α9蛋白質表現的影響 ….………….……. 49
九、 10 μM Nicotine對於MDA MB-231中蛋白質表現影響的最佳作用時間 …….………….…….…………….50
十、 在MDA MB-231乳癌細胞株中,各別加入Quercetin、Luteolin或兩者合併使用 pretream後具有抑制加入 Nicotine後,其內蛋白質表現的情形 ........….…51
十一、 Luteolin 及Quercetin各別或混合pretream對於加入Nicotine後在MDA MB-231乳癌細胞株中其蛋白質表現之比較 ………………….……………..52
十二、 混合或單獨使用Luteolin 及Quercetin pretream對於抑制Nicotine誘發MDA MB-231乳癌細胞株蛋白質表現之比較 ……………………………….……………. 53
十三、 Luteolin 及Quercetin pretream後抑制Nicotine誘發轉錄因子 對於nAchR α9 promoter 的影響 …………54
十四、 以Soft agar assay ( Colony formation assay ) 觀察Luteolin 及Quercetin抑制MDA MB-231乳癌細胞株Transformation的發生 ……………….………….55

第四章 討論 ( Discussion ) ……………………………………… 57
第五章 圖表 ( Figures ) …………………………………………… 64
Fig 1. MDA MB-231 cells hyperplasia by nicotine concentration increase. ……………………………………..…65
Fig 2 A.B.C. Different concentration of quercetin and luteolin inhibit in MDA MB-231 cells proliferation. ……………..66
Fig 3. Combination effect comparision of quercetin and luteolin inhibition in MDA MB-231 cells proliferation. ……….68
Fig 4. The expressions of nAchR α9 mRNA in MDA MB-231 breast cancer cells with Nicotine. ……………………………….69
Fig 5. The expressions of different time of nAchR α9 mRNA in MDA MB-231 breast cancer cells with 10 μM nicotine. ………70
Fig 6. Comparision of nAchR α9 mRNA expression in MDA MB-231 breast cancer cells with different compounds. ... ……71
Fig 7. Comparision of nAchR α9 mRNA in MDA MB-231 breast cancer cells of pre-treatment with different compounds. ….72
Fig 8. The expressions of nAchR α9 in MDA MB-231 breast cancer cells with nicotine. ……………………………………73
Fig 9. The expressions of different time of nAchR α9 in MDA MB-231 breast cancer cells with nicotine. ………………………74
Fig 10 A.B.C. Effects of quercetin and luteolin inhibition in MDA MB-231 cells expression with nicotine respectively. .……75
Fig 11. Comparision of quercetin and luteolin inhibition in MDA MB-231 cells expression with nicotine. ………………….77
Fig 12. Comparision of quercetin and luteolin inhibition in MDA MB-231 cells expression with nicotine. .………………78
Fig 13. Effects of 10 μM nicotine and 25 μM luteolin ,25 μM quercetin on full length nAchR α9 promoter. ………………79
Fig 14. Quercetin and/or luteolin could inhibit the ability of colonies formation in MDA MB-231 cells. …………………….80

第六章 參考文獻 ( References ) ………………………………… 82

附錄 ( Appendices ) ……………………………………93
The chemical structures of nicotine, quercetin and luteolin ……94
pGL3 vector map ……………………………………95
本篇論文結構圖 ……………………………………96
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