請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52302完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳燕惠 | |
| dc.contributor.author | Shang-Hsun Tsou | en |
| dc.contributor.author | 鄒尚勳 | zh_TW |
| dc.date.accessioned | 2021-06-15T16:11:24Z | - |
| dc.date.available | 2020-09-24 | |
| dc.date.copyright | 2015-09-24 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-18 | |
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Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406: 747-752. 139. Gordon LA, Mulligan KT, Maxwell-Jones H, Adams M, Walker RA, Jones JL (2003) Breast cell invasive potential relates to the myoepithelial phenotype. Int J Cancer 106: 8-16. 140. Walter RB, Raden BW, Hong TC, Flowers DA, Bernstein ID, Linenberger ML (2003) Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells. Blood 102: 1466-1473. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52302 | - |
| dc.description.abstract | 癌細胞產生對於單一或是多種化療藥物的抵抗作用稱為多重抗藥性(MDR)。多重抗藥性的發生是化學治療失敗的重要原因，其細胞機制涉及轉運蛋白表現，增強排除藥物至細胞外的功能、並減少藥物進入細胞的量，或藉由變更藥物標的、抑制細胞凋亡程序、增進細胞DNA受損後修復能力、活化解毒與藥物代謝基因來達成。對於多重抗藥性的研究，過去多是探討野生型與多重抗藥性型癌細胞的各種表現差異，但對於發生過程的機轉仍不清楚。本研究利用人類乳癌細胞株MCF-7野生型 (MCF-7/WT) 作為起始，建立一系列對doxorubicin有抗藥性的細胞株，來探討誘發多重抗藥性過程中有哪些基因參與其中? 而其相互關係如何? 本實驗室將MCF-7/WT培養在含1 nM doxorubicin的培養基中，待細胞生長穩定後，增加藥物濃度，以二的次方的doxorubicin濃度篩選具有抗藥性的細胞株稱為MCF-7/ADR-n，n為1 nM的倍數。總共建立了MCF-7/ADR-1、MCF-7/ADR-2、MCF-7/ADR-4、MCF-7/ADR-8、MCF-7/ADR-16、MCF-7/ADR-32、MCF-7/ADR-64、MCF-7/ADR-128、MCF-7/ADR-256、MCF-7/ADR-512、MCF-7/ADR-1024等11個不同抗藥性程度的細胞株。細胞培養的終點止於MCF-7/ADR-1024，其與抗藥型細胞株MCF-7/ADR具有相同程度的抗藥性及P-glycoprotein (P-gp)表現。研究結果發現MCF-7 / ADR-1024和MCF-7 /ADR具有相近的細胞型態與DNA倍體狀態。基因表現方面，MCF-7/ADR-1024和MCF-7/ADR在細胞修復基因p53、BRCA1/2，細胞凋亡相關基因Bcl-2和上皮-間葉轉換（EMT）的上皮特徵基因E-cadherin的基因表表現量皆下降;而解毒酶GST-π與蛋白激酶PKC-α表達皆上升。上皮特徵基因E-cadherin表現下降以及間葉特徵基因N-cadherin、Slug、Twist，與 Vimentin的表現上升，證實抗藥性發生過程中上皮-間葉特性發生轉化。此外，MCF-7/ADR-1024經PI3K / AKT抑製劑wortmannin處理後，上皮-間葉特徵基因Slug, Twist表現量下降及轉運蛋白P-gp表現量下降。MCF-7 / ADR-1024和MCF-7 /ADR有相似的微球體形成能力及癌幹細胞特徵簇群CD44 high/CD24 low。同時，具有相同突變形式的p53基因，兩者皆缺失密碼子127-133。更進一步證實突變型p53參與了抗藥性發生的過程。本研究將MCF-7/ADR中帶有缺失密碼子127-133的突變型p53基因轉殖進入MCF-7/WT野生型，建立MCF-7/del p53細胞株。結果發現MCF-7/del p53能表現轉運蛋白P-gp，並顯著活化MDR-1啟動子。以NF-κB抑制劑cyclosporine處理，MCF-7/del p53對於doxorubicin的敏感性會增加。此外MCF-7/del p53與MCF-7/ADR細胞型態近似;間葉特徵基因Slug、Vimentin表現上升而上皮特徵基因CDH1表現下降。與MCF-7/WT比較，MCF-7/del p53具有高度的遷徙能力，癌幹細胞特徵簇群表現與微球體形成能力增加。因此具缺失密碼子127-133的突變型p53基因可能是藉由活化NF-κB信號傳導及MDR-1啟動子、並影響上皮-間葉轉化與癌幹細胞特徵表達，來參與多重抗藥性的發生。 結論 多重抗藥性發生過程中，在篩選劑量為1.024 μM doxorubicin下，P-gp才得以表現。P-gp的表現與一些相關基因的表現或是突變有關，這些基因如DNA修復基因，抗細胞凋亡基因、代謝解毒基因、上皮-間葉轉化基因等。因此，本論文提出兩種可能的多重抗藥性的建立機制。模式一、篩選自癌幹細胞特徵簇群; 模式二、突變累積導致抗藥性表現。無論模式為何，皆是在1.024 μM doxorubicin處理下才有的變化。藉由篩選自癌幹細胞特徵族群外，p53突變亦參與抗藥性發生，證實突變的累積亦是造成抗藥性發生的原因。因此，針對癌幹細胞特徵或是突變基因作為藥物設計的標的，在未來癌症治療上將有相當助益。 | zh_TW |
| dc.description.abstract | Cellular mechanisms of multidrug resistance (MDR) are related to ABC transporters, apoptosis, antioxidation, drug metabolism, DNA repair and cell proliferation. It remains unclear whether the process of resistance development is programmable. I aimed to study gene expression profiling circumstances in MCF-7 during MDR development. Eleven MCF-7 sublines with incremental doxorubicin resistance were established as a valued tool to study resistance progression. MDR marker P-gp was overexpressed only in cells termed MCF-7/ADR-1024 under the selection dose approaching 1024 nM. MCF-7/ADR-1024 and authentic MCF-7/ADR shared common features in cell morphology and DNA ploidy status. MCF-7/ADR-1024 and authentic MCF-7/ADR showed downregulation of DNA repair genes BRCA1/2 and wild type p53, apoptosis-related gene Bcl-2 and epithelial-mesenchymal transition (EMT) epithelial marker gene E-cadherin; Whereas, detoxifying enzymes glutathione-S transferase-π and protein kinase C-α were up-regulated. The genes involved in EMT mesenchymal formation were also overexpressed, including N-cadherin, vimentin and the E-cadherin transcription repressors Slug, Twist and ZEB1/2. PI3K/AKT inhibitor wortmannin suppressed expression of Slug, Twist and MDR-1. In addition, MCF-7/ADR-1024 cells exerted CSC-like cell surface marker CD44 high/CD24 low and form mammospheres. Mutant p53 with a deletion at codons 127-133 markedly appeared in MCF-7/ADR-1024 and authentic MCF-7/ADR as well. In order to understand if p53 mutation is related to drug resistance development, a del p53-containing construct was transfected into MCF-7/WT to generate the MCF-7/del p53 which stably expressed del p53. Results showed that MCF-7/del p53 acquired resistance to doxorubicin with increased P-gp efflux function. The MDR-1 promoter was significantly activated by external or integrated del p53 using transient expression assay (p < 0.001). Inhibition of NF-κB by cyclosporine sensitized MCF-7/del p53 cells to doxorubicin toxicity. In addition, morphology of MCF-7/del p53 and MCF-7/adr were alike. EMT was observed in MCF-7/del p53 cells with regard to presence of mesenchymal markers Slug and Vimentin and the decrease in epithelial marker CDH1, as well as significant migration ability (p < 0.001). Furthermore, expression of cancer stem cell-like marker CD44 increased, accompanying with mammosphere formation. Altogether, expression of del p53 renders MCF-7/del p53 to acquire doxorubicin resistance characteristics as MCF-7/adr but less effectively. del p53 may be an important factor for the non-invasive MCF-7 to activate NF-κB signaling and MDR-1 promoter and partly attribute to EMT and stem cell-like properties so as to facilitate drug resistance. Conclusion Resistance marker P-gp arises owing to turn on/off or mutation of the genes involving in DNA repair, apoptosis, detoxifying enzymes, EMT and ABC transporters at a turning point (1.024 μM doxorubicin challenge). Behind this point, no obvious alterations were found in most tested genes. Selection for CSC-like cells under this dose may also importantly attribute to propagation of the population presenting invasive properties and drug resistance. Thereby, two models are suggested in the induction of drug resistance. Model 1: Selection for CSC-like cells and model 2: Mutations for gain-of-resistance. The acclamation of mutations facilitates drug resistance development. del p53 may play a role in drug resistance. Drugs designs for targeting the cancer stem cell characteristics or mutated genes involved in drug resistance will be useful in cancer treatment. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T16:11:24Z (GMT). No. of bitstreams: 1 ntu-104-D97423001-1.pdf: 13129822 bytes, checksum: 77673d5ed3f26fd962a0f3ea24e88dc0 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 中文摘要 I Abstract III Table of Contents VI List of Figures Tables IX Abbreviations XII Chapter 1. Introduction 1 1.1 Multidrug Resistance 2 1.2 Transporters 4 1.2.1 MDR-1 5 1.2.2 MRP-1 7 1.3 Apoptosis 8 1.4 DNA Repair 9 1.5 p53……………….. 10 1.6 NF-κB… 12 1.7 Detoxification 14 1.8 PI3K-AKT 15 1.9 EMT….. 17 1.10 CD44… 18 1.11 CSCs… 19 1.12 Specific aims of the study 20 Chapter 2. Materials and Methods 26 2.1 Antibodies and chemicals 27 2.2 Cell lines and cell culture 29 2.3 MTT assay 30 2.4 RT-PCR 31 2.5 Ploidy composition analysis 32 2.6 Western blot analysis 33 2.7 Flow cytometry analysis of MDR-1 function 34 2.8 Full-length p53 cDNA sequencing 35 2.9 Detection of intracellular ROS levels 36 2.10 Wound-healing assay 37 2.11 Flow cytometry for cancer stem cells markers CD44 and CD24 38 2.12 Colony formation assay 39 2.13 Construction of the plasmid pcDNA3.1 containing del p53 and establishment of the del p53 stably expressing cell line MCF-7/del p53 40 2.14 Construction of the expression vector containing MDR-1 promoter 42 2.15 Transient expression assay 43 2.16 Statistical analysis 44 Chapter 3.Results 45 3.1 Establishment of a series of MCF-7 cell lines with incremental strength of resistance to doxorubicin 46 3.2 Gene expression and DNA ploidy status of MCF-7/WT, MCF-7/ADR-1024 and MCF-7 /ADR cell lines 47 3.3 The MDR-1 gene is expressed in MCF-7/ADR-1024 and the MRP-1 gene is mainly expressed in MCF-7/ADR-128 and MCF-7/ADR-256 48 3.4 Low expression of Bcl-2 in doxorubicin-resistant cells 49 3.5 Repair genes BRCA1/2 and wild type p53 are down-regulated in the development of doxorubicin resistance 50 3.6 Involvement of detoxifying genes Nrf-2, GST-π and PKC-α in doxorubicin-induced resistance 52 3.7 Epithelial to mesenchymal transition in MCF-7/ADR-1024 54 3.8 Association of PI3K/AKT pathway with EMT properties and drug resistance in MCF-7/ADR-1024 55 3.9 Presence of cancer stem cell-like properties upon doxorubicin selection 57 3.10 Epithelial-mesenchymal transition and tumorigenic properties in MCF-7/WT treated with high dose doxorubicin. 59 3.11 Establishment of the MCF-7/del p53 cell line stably expressing del p53 60 3.12 MCF-7/del p53 cells acquire resistance to doxorubucin 61 3.13 del p53-mediated P-gp function is associated with MDR-1 promoter activation and NF-κB expression 63 3.14 Epithelial-mesenchymal transition is induced in MCF-7/del p53 cells 65 3.15 MCF-7/del p53 carrying cancer stem cell-like properties 66 Chapter 4. Discussion 96 4.1 A critical dose of doxorubicin is required to alter the gene expression profiles in MCF-7 cells acquiring multidrug resistance 97 4.2 Mutated p53 gene with 21 bp deletion confers susceptibility to gain-of-function for multidrug resistance in MCF-7 cells 104 4.3 Conclusion 111 Figures Tables Figure 1-1. Cellular mechanisms of multidrug resistance. 21 Figure 1-2. The phenotypic effects of TP53 mutations. 22 Figure 1-3. Schematic representation of EMT-related genes expression pattern in drug resistant cells. 23 Figure 1-4. EMT results in cells with stem-like properties. 24 Figure 1-5. The cancer stem cell hypothesis. 25 Figure 3-1. The resistance index in doxorubicin-resistant MCF-7 cell lines. 67 Figure 3-2 Differential gene expression and DNA ploidy status of the MCF-7 derived cell lines. 68 Figure 3-3. ABC transports are upregulated in the induction of drug resistance. 70 Figure 3-4. Expression profiles of apoptosis-related genes in the series of resistant cells. 71 Figure 3-5. Repair genes BRCA1/2 and wild type p53 are downregulated in the development of doxorubicin resistance. 72 Figure3- 6. Detoxifying genes Nrf-2, GST-π and PKC-α are associated with doxorubicin-induced resistance. 75 Figure 3-7. EMT processes in the induction of doxorubicin resistance. 77 Figure3- 8. Association of PI3K/AKT pathway with EMT properties and drug resistance. 79 Figure 3-9. Expression of CD44 isoforms is associated with doxorubicin-induced resistance. 80 Figure 3-10. Presence of cancer stem cell-like properties upon doxorubicin selection. 82 Figure 3-11. Epithelial-mesenchymal transition and tumorigenic property could be induced in the transient treatment with high dose of doxorubicin. 83 Figure 3-12. Cloning of MCF-7/del p53 stably expressing del p53. 84 Figure 3-13. MCF-7 /del p53 acquiring resistance to doxorubicin. 86 Figure 3-14. del p53-mediated P-gp function is associated with MDR-1 promoter activation and NF-κB expression. 89 Figure 3-15. del p53 is involved in EMT properties. 92 Figure 3-16. MCF-7/del p53 cells express cancer stem cell-like properties. 95 Table 4-1. Expression of mutidrug resistance-related genes in the series of MCF-7/ADR-n cell lines. 113 Figure 4-1. Up/down regulation of multidrug resistance-related genes in the time line of MCF-7/ADR-1024 development. 114 Figure 4-2. Two models illustrate development of doxorubicin resistance. 115 References 116 Appendices 129 Supplementary Table S1. Primer sequences for RT-PCR 130 Supplementary Table S2. Drug-resistance-related genes screened in this study 134 | |
| dc.language.iso | en | |
| dc.subject | P-糖蛋白 | zh_TW |
| dc.subject | 上皮-間葉轉化 | zh_TW |
| dc.subject | 突變型p53基因 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 乳癌 | zh_TW |
| dc.subject | 磷脂?肌醇3激? | zh_TW |
| dc.subject | 細胞核因子B | zh_TW |
| dc.subject | 癌幹細胞特徵 | zh_TW |
| dc.subject | 艾黴素 | zh_TW |
| dc.subject | Doxorubicin | en |
| dc.subject | Cancer stem cell-like cells | en |
| dc.subject | Mutant p53 | en |
| dc.subject | Epithelial-mesenchymal transition | en |
| dc.subject | P-glycoprotein | en |
| dc.subject | Apoptosis | en |
| dc.subject | Breast cancer | en |
| dc.subject | PI3K | en |
| dc.subject | NF- | en |
| dc.title | 乳癌細胞株MCF-7引發多重抗藥性之機轉探討 | zh_TW |
| dc.title | The Mechanisms of Multidrug Resistance Development in the Breast Cancer Cell Line MCF-7 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 駱雨利,許麗卿,楊家榮,張國友 | |
| dc.subject.keyword | 癌幹細胞特徵,突變型p53基因,上皮-間葉轉化,P-糖蛋白,艾黴素,細胞凋亡,細胞核因子B,磷脂?肌醇3激?,乳癌, | zh_TW |
| dc.subject.keyword | Cancer stem cell-like cells,Mutant p53,Epithelial-mesenchymal transition,P-glycoprotein,Doxorubicin,Apoptosis,NF-,PI3K,Breast cancer, | en |
| dc.relation.page | 166 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-08-18 | |
| dc.contributor.author-college | 藥學專業學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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