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博碩士論文 etd-0520117-130700 詳細資訊
Title page for etd-0520117-130700
論文名稱
Title
評估長期暴露鄰苯二甲酸(2-乙基己基)酯對阿黴素抗乳腺癌細胞之影響
The impacts of prolonged di(2-ethylhexyl)phthalate exposure on doxorubicin-induced anti-breast cancer cells
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
80
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2017-04-21
繳交日期
Date of Submission
2017-06-21
關鍵字
Keywords
表觀基因調節、ABC轉運蛋白、抗藥性、乳腺癌、阿黴素、鄰苯二甲酸二(2-乙基己基)酯
Di(2-ethylhexyl) phthalate, DEHP, doxorubicin, breast cancer, chemoresistance, transporter proteins, epigenetic modulation
統計
Statistics
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The thesis/dissertation has been browsed 5709 times, has been downloaded 71 times.
中文摘要
鄰苯二甲酸二(2-乙基己基)酯(di(2-ethylhexyl)phthalate, DEHP)是鄰苯二甲酸酯衍生物之一,被廣泛運用在工業及民生用品中的塑化劑。近年來,台灣學者檢測出民眾體內DEHP代謝物含量遠高於歐美國家,顯示大眾生活容易接觸到含有DEHP之物品。過去研究指出DEHP屬於環境荷爾蒙干擾物之一,具有結合雌激素受體特性可干擾人體內分泌系統,也證實鄰苯二甲酸酯衍生物會提高罹患乳腺癌的風險,以及影響乳腺癌的基因表現。目前多數DEHP的研究都著重在DEHP對乳腺癌生成或轉移的影響,而對於DEHP是否影響癌症抗藥性的相關討論則尚未有完整的報導。在本篇研究中,長期暴露DEHP的MDA-MB-231和MCF-7對阿黴素(doxorubicin, Dox)的反應是不相同的,MDA-MB-231有顯著抵抗Dox的現象,而MCF-7則沒有對Dox產生顯著抗藥性。長期暴露DEHP在MDA-MB-231細胞中,發現整體DNA甲基化程度上升,兩個抑癌基因PTEN、GSK3β和促細胞凋亡因子BAX蛋白質表現量明顯下調,以及ABC轉運蛋白ABCB1 表現的增加。總結,目前研究顯示DEHP長期暴露使MDA-MB-231細胞獲得抵抗抗癌藥物Dox的能力,可能是DEHP對乳腺癌細胞表觀基因層次如甲基化而導致的影響,未來將進一步去探討乳腺癌多重抗藥性產生與DEHP長期暴露改變細胞內表觀基因調節的關聯性。
Abstract
Di(2-ethylhexyl)phthalate (DEHP), a phthalate derivative, is the most commonly used as plasticizers for industrial and consumer equipment. In recent years, Taiwan scholars had detected that the content of DEHP metabolites in Taiwanese population was higher than that in European and American countries. Previous studies indicated that DEHP belonged to endocrine disruptor and its metabolites could increase the risk of developing breast cancer. Many studies focused on the estrogenic impact of phthalates on the onset or the metastasis of breast cancer, however, little was known regarding the roles of phthalates in acquired chemoresistance of breast cancer. In our study, MDA-MB-231 cells, but not MCF-7 cells, significantly resisted to doxorubicin treatment in prolonged DEHP exposure. In MDA-MB-231 cells, the level of global DNA methylation was up-regulated and the protein expression of tumor suppressors PTEN and GSK3β, and pro-apoptotic BAX were down-regulated following the long-term exposure of DEHP. Our results also showed that DEHP exposure led to a moderate increase of ABCB1 expression, especially at the mRNA level. In conclusion, our results imply that prolonged DEHP exposure affected the response of breast cancer to doxorubicin. In the future, we will further clarify the mechanism of DEHP-mediated chemoresistance, especially through the epigenetic regulation in breast cancer cells.
目次 Table of Contents
國立中山大學研究生學位論文審定書 i
致謝 ii
中文摘要 iii
Abstract iv
縮寫表 3
中英文對照表 5
1. 研究背景 6
1.1 現今乳腺癌趨勢 6
1.2 乳腺癌潛在的危險因子 6
1.3 乳腺癌亞型之分類 8
1.4 乳腺癌治療方法 9
1.5 癌細胞產生抗藥性機制 12
1.6 鄰苯二甲酸酯對人體之影響 14
1.7 阿黴素背景介紹 15
研究動機 17
2. 實驗物品與方法 18
2.1 藥物來源 (Drug source) 18
2.2 細胞培養 (Cell culture) 18
2.3 細胞群落試驗 (Colony Formation assay) 18
2.4 藥物排出試驗 (Drug efflux assay) 19
2.5 反轉錄聚合酶連鎖反應 (Reverse transcribed polymerase chain reaction,RT-PCR) 19
2.6定量即時聚合酶連鎖反應 (Quantitative real-time polymerase chain reaction) 20
2.7 氧化壓力試驗 (Oxidative Stress assay) 21
2.8 高通量西方墨點微陣列 (Micro-Western Array) 22
2.9 乳腺癌細胞異體移植之斑馬魚模式 (Zebrafish breast cancer xenografts model) 22
2.10 整體基因組DNA甲基化評估 (Global DNA methylation) 23
3. 實驗結果 25
3.1長期暴露DEHP對乳腺癌細胞抵抗Dox能力之評估 25
3.2長期暴露DEHP對乳腺癌細胞排出Dox能力之評估 26
3.3長期暴露DEHP對Dox誘導氧化壓力產生之影響 26
3.4長期暴露DEHP之clones篩選 27
3.5長期暴露DEHP可調控轉運蛋白的蛋白質和mRNA表現量 28
3.6長期暴露DEHP之clones的Micro-Western Array 28
3.7在斑馬魚模式中,長期暴露DEHP之clones對Dox之影響 28
3.8長期暴露DEHP之clones的整體基因組DNA甲基化程度 29
4. 討論 30
5. 結論 34
6. 圖 35
圖一. 短期暴露DEHP之乳腺癌細胞株對Dox較無明顯耐藥性 37
圖二. 長期暴露DEHP之MDA-MB-231對Dox有較明顯耐藥性 39
圖三. 長期暴露DEHP增強MDA-MB-231排出Dox的能力 43
圖四. 長期暴露DEHP抑制MCF-7的細胞內吞作用 45
圖五. 長期暴露DEHP之MDA-MB-231可抑制Dox誘導的ROS 48
圖六. 長期暴露DEHP之的clones具有顯著對Dox之耐藥性 50
圖七. 長期暴露DEHP對轉運蛋白表現量的改變 53
圖八. 長期暴露DEHP對轉運蛋白mRNA表現量的改變 56
圖九. 長期暴露DEHP之MDA-MB-231生長相關因子蛋白質的表現程度熱度圖(heat map) 57
圖十. 長期暴露DEHP之MDA-MB-231的clone 1在斑馬魚模式中具有顯著對Dox的耐藥性 58
圖十一. 長期暴露DEHP之MDA-MB-231 clones的整體基因組DNA甲基化程度 59
7. 附錄 60
8. 文獻參考 65
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