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研究生:王貝嘉
研究生(外文):Pei-Chia
論文名稱:雌二醇之代謝物(2-甲基氧雌二醇)抑制乳癌細胞侵入能力及誘導細胞凋亡之機制探討
論文名稱(外文):Study of the mechanism of estradiol metabolite 2-methoxyestradiol on the anti-metastasis and inducing apoptosis of breast cancer cells
指導教授:鄭鈞文鄭鈞文引用關係
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:生化暨生物科技研究所
學門:生命科學學門
學類:生物科技學類
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:98
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癌細胞的轉移是惡性腫瘤的重要特徵,也是致死的主要原因,且在臨床的治療也最為複雜。有鑑於此,研究天然藥物抑制癌細胞轉移便有其臨床上的重要意義。2-甲基氧雌二醇(2-methoxyestradiol)為17β 雌二醇(estradiol)的代謝產物。研究指出,2-甲基氧雌二醇具有抗腫瘤、抗血管新生、抑制腫瘤增生並有利於促使癌細胞走向凋亡。但是到目前為止,對於2-甲基氧雌二醇抑制乳癌細胞增生、轉移甚至於誘導癌細胞凋亡之機轉並未有詳細完整的研究發表。本研究論文則是以2-甲基氧雌二醇為研究標的探討對人類乳癌細胞株Hs 578T其抗腫瘤的作用機轉。結果發現當2-甲基氧雌二醇隨著處理時間越長,可抑制乳癌細胞的生長。以DAPI 染色與DNA斷裂分析方法,發現2-甲基氧雌二醇會導致染色質濃縮(chromatin condensation)、DNA斷裂並進一步促使癌細胞死亡。另外,2-甲基氧雌二醇會調控Bax/Bcl-2 蛋白表現影響粒線體功能使癌細胞走向凋亡。其間,發生粒線體膜電位的損失、細胞色素c釋放及caspase 9、3的活性增加。另一方面,2-甲基氧雌二醇會降低cyclin D, cyclin E, cyclin A 和cyclin B表現而抑制Hs 578T細胞株的增生能力,其作用機轉乃是調節抑制 PI3K/Akt和GSK-3β/β-catenin的訊息調控。甚者,2-甲基氧雌二醇會透過抑制IκB kinase的活性,影響NF-κB的轉錄活化啟動而降低MMP-2表現,進而抑制Hs 578T細胞株的侵襲及轉移。綜合上述,2-甲基氧雌二醇具有抑制乳癌細胞侵襲、轉移及增生的能力並且能夠誘導癌細胞的凋亡。

2-Methoxyestradiol (2-MetE2), an endogenous estrogen metabolite of 17-beta estradiol, has been reported to effect on suppression of tumor cell malignancy. However, the molecular mechanisms underlying 2-MetE2 on growth inhibition, metastasis and apoptosis induction are still unknown. The aim of this study is to investigate the anti-tumor effects of 2-MetE2 in human breast cancer cells. Compared with untreated controls, treatment of Hs578T cells with 2-MetE2 increased chromatin condensation, DNA fragmentation and cell apoptosis. 2-MetE2 exposure resulted in collapse of mitochondrial membrane potential, accompanied by altered ratio of Bax/Bcl-2, release of cytochrome c and activation of caspase-9/3. In addition, 2-MetE2 inhibited cell invasiveness and migration on Hs 578T cells through decreased activity of matrix metalloproteinase 2 (MMP-2) was ascribed to IkB kinase inactivation. Treatment of 2-MetE2 resulted in an inhibition of the PI3K-Akt/PKB survival pathway in Hs 578T cells. Moreover, prohibition of cell proliferation on 2-MetE2-treat Hs 578T cells through decreased of cyclin D, cyclin E, cyclin A and cyclin B expression. In conclusion, our study of the effect on 2-MetE2 on anti-proliferation, anti-invasion, anti-migration, and apoptosis suggests that 2-MetE2 is a potential agent for treating breast cancer.




壹、中文摘要…………………………………………………2
英文摘要…………………………………………………4
貳、縮寫………………………………………………………6
參、緒論………………………………………………………7
肆、研究動機…………………………………………………28
伍、實驗材料與方法…………………………………………29
陸、實驗結果…………………………………………………52
柒、討論………………………………………………………63
捌、參考文獻…………………………………………………68
玖、圖表與圖表說明…………………………………………78
拾、附圖表…………………………………………………....94





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