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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 梁博煌(Po-Huang Liang) | |
dc.contributor.author | Wei-Ting Tian | en |
dc.contributor.author | 田偉廷 | zh_TW |
dc.date.accessioned | 2021-06-16T17:27:15Z | - |
dc.date.available | 2017-08-20 | |
dc.date.copyright | 2012-08-20 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-16 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64032 | - |
dc.description.abstract | 乳癌為全球婦女最常被診斷為惡性腫瘤的癌症,大部份(大於75%)的乳癌具有雌激素受體。雌激素目前已廣泛地被認為會促成腫瘤生成及腫瘤惡化。此外,在臨床上已普遍地偵測到乳癌患者的caspase-3在表現量有下降的情形,也被推論為是造成抗藥性的可能機轉。然而,目前對於造成caspase-3表現量下降的分子機轉仍不明瞭。在這份研究中,我們對雌激素促使腫瘤生成及腫瘤惡化是否是經由造成caspase-3表現量下降進行探討,並深入探討在乳癌細胞中雌激素造成 caspase-3表現量下降的分子機轉為何。
我們發現以雌激素處理乳癌細胞,會使得具雌激素受體的T47D乳癌細胞產生caspase-3表現量下降及多重抗藥性的情形,而不具雌激素受體的MDA-MB-231乳癌細胞則不會有這種現象發生。目前已經有報導指出以雌激素進行處理會造成miR-let-7a1表現量的上升,同時也有報導指出miR-let-7a1可藉由標的caspase-3而抑制治療所引起的細胞凋亡。我們也發現在我們處理細胞雌激素時,miR-let-7a1的表現量有上升的趨勢,同時強迫表達miR-let-7a1的T47D也產生caspase-3表現量下降及多重抗藥性的性狀。因此,我們想進一步釐清雌激素是如何促使miR-let-7a1表現量提升的分子機轉。不同於我們用IPA軟體所預測的結果,我們發現c-Myc/ERα複合體可能不是或非主要造成miR-let-7a1表現量上升的原因。由於在miR-let-7a1的promoter區域具有雌激素受體α的結合位點,之後必須進行ChIP的實驗去釐清雌激素受體是否會直接結合在這個區域進而促其表現上上升。 在我們的實驗中,我們發現活化態的caspase-7(p19/p12)在caspase-3表現量下降的乳癌細胞中表現量有提升的趨勢,同時雌激素所引起的caspase-3表現量下降的T47D也具有相同的性狀。我們進一步依循IPA軟體的預測去探討其可能的分子機轉為何。然而,STAT3及RB1兩者在以雌激素進行處理T47D時,都沒有產生明顯入核的情形。於是,我們進一步分析caspase-7的promoter區堿,發現其上也具有雌激素受體的結合位點。之後必須進行ChIP的實驗去釐清雌激素受體是否會直接結合上caspase-7的promoter區域進而促其表現上升。 目前我們實驗室已經發現蛋白質間交互作用的抑制劑I-Lys可以打破XIAP: p19/p12-casp7複合體的交互作用,進而促使惡性乳癌細胞走向細胞凋亡。 在我們的實驗中,我們也發現相較於未經處理的細胞,雌激素所引起的caspase-3表現量下降的T47D對I-Lys較為敏感。由目前所得到的結果可得知雌激素如何促使腫瘤生成及腫瘤惡化及雌激素如何調節乳癌細胞中caspase-3表現量下降而caspase-7表現量上升的情形。此外, XIAP:p19/p12-casp7複合體也可以作為對抗caspase-3表現量下降的惡性腫瘤的標靶。值得注意地,我們也建議醫療上以激素替代療法(HRT)的治療停經後婦女以防止由於雌激素水平下降的不適時需格外地小心。 | zh_TW |
dc.description.abstract | Breast cancer is the most common malignancy diagnosed in women worldwide. Most of breast cancers (> 75%) were ER+. It is well-known that estrogen can promote tumorigenesis and cancer cells progression. Besides, caspase-3 down-regulation (CASP3/DR) has been extensively detected in clinical breast cancers and thought to be possible mechanism for chemoresistance. However, the molecular mechanism underlying CASP3/DR remains unknown. In this study, we investigate if estrogen stimulates cancer progression and chemoresistance through CASP3/DR and exploring molecular mechanism underlying estrogen-induced CASP3/DR in breast cancer cells.
We found a multidrug-resistant phenotype and reduced CASP3 expression in estrogen treated ER+T47D but not in treated ER-MDA-MB-231 breast cancer cells. It has been reported estrogen treatment would lead to miR-let-7a1 up-regulation andmiR-let-7a1 targeting caspse-3 would suppress therapeutic-induced death. We further found that miR-let-7a1 expression level was elevated during estrogen treatment and T47D enforced expressing miR-let-7a1 also exhibited CASP3/DR and chemoresistant phenotype. Therefore, we aimed to elucidate the molecular mechanism of how estrogen promotes miR-let-7a1 expression. Different from IPA analysis, we found ERα/c-Myc complex may not be responsible for promoting miR-let-7a1expression or just plays a minor role since c-Myc failed to show significant translocation during exposure to estrogen. ERα would regulate miR-let-7a1 expression by directly binding to the promoter region of miR-let-7a1, which needs to be confirmed by ChIP assay. We had found active-caspase-7 (p19/p12) was elevated in CASP3/DR breast cancer cells previously and as shown here estrogen-induced CASP3/DR T47D revealed similar phenotype. We further explored the molecular mechanism using IPA software to analyze that p-STAT3 and RB1 might be involved. However, both p-STAT3 and RB1 did not show significant translocation. However, we identified there are ERα binding sites in the promoter region of CASP7, suggesting that ERα would regulate CASP7 expression by directly binding to this region, which also needs to be confirmed by ChIP assay. Previously, we had identified the protein-protein interaction (PPI) inhibitor I-Lys could disrupt the XIAP: p19/p12-casp7 complex to promote the malignant breast cancer cell apoptosis. Here I show estrogen-induced CASP3/DR T47D cells were more sensitive to I-Lys compared to the untreated. The collected data answer how estrogen promote cancer progression and chemoresistance and which estrogen regulates CASP3/DR and caspase-7 up-regulation in breast cancer cells. Besides, these findings suggest the implication of targeting XIAP: p19/p12-casp7 complex in combating CASP3/DR malignancies. Importantly, it also recommends a caution of using hormone replacement therapy (HRT) in treating post-menopause women in order to prevent discomfort due to declined estrogen levels. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T17:27:15Z (GMT). No. of bitstreams: 1 ntu-101-R99b46015-1.pdf: 2574546 bytes, checksum: 249d3d30ae20ed32f664e0e08b3b5168 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 口委審定書……………………………………………………………………………i
誌謝……………………………………………………………………………………ii 中文摘要……………………………………………………………………………...iii ABSTRACT...………………………………………………………………………....v (1) INTRODUCTION 1.1 Treatments for breast cancer....……………………………………………….1 1.2 Estrogen signaling……………………………………………………………5 1.3 Caspase family and their functions in apoptosis……………………………10 1.4 MicroRNA…………………………………………………………………..13 1.5 Previous studies and present works…………………………………………15 (2) MATERIALS AND METHODS 2.1 Antibodies..……………………………………………………………….....18 2.2 Cell culture………………………………………………………………….18 2.3 protein preparation………………………………………………………….19 2.4 Western blot analysis………………………………………………………..20 2.5 Flow cytometric analysis……………………………………………………20 2.6 Stable cell line generation…………………………………………………..21 2.7 Gene expression level analysis……………………………………………...21 2.8 Collection of Clinical Samples……………………………………………...22 2.9 Statistical analyses…………………………………………………………..23 (3) RESULTS 3.1 Long-termed exposure to estrogen causes chemoresistance and CASP3/DR of ER+ T47D breast cancer cell line………………………………………..24 3.1.1 Long-termed estrogen treatment promotes chemoresistance of ER+T47D breast cancer cells…………………………………………24 3.1.2 Long-termed estrogen treatment causes CASP3/DR in ER+ T47D breast cancer cell……………………………………………………..24 3.1.3 Estrogen elevates the expression of miRNA let-7a1whcih inhibits posttranscriptional processing of caspase-3………………………….25 3.2 Estrogen-induced CASP3/DR is through estrogen receptor alpha signaling.27 3.2.1 Estrogen receptor alpha (ERα) signaling leads to miR-let-7a1 up-regulation…………………………………………………………27 3.2.2 Estrogen receptor alpha ( ERα ) translocates into nucleus during the estrogen treatment……………………………………………………27 3.2.3 Estrogen receptor alpha promote pri-miRNA let-7a transcription……28 3.2.4 Ligand-bound ERα might directly bind to the promoter region of miR-let-7a1 to promote its expression……………………………….29 3.2.5 Clinical relevances of the elevated miR-let-7a1 and CASP3/DR to prognosis of breast cancer patients…………………………………...29 3.3 Caspase-7 expression is enhanced and the XIAP/p19/p12-casp7 complexes constitutively accumulate in ER-positive breast cancer cells post-treatment with E2……………………………………………………………………...30 3.3.1 Estrogen treatment increases caspase-7 expression and promotes accumulation of active-form caspase-7 (p19/p12-casp7) retrained by its endogenous inhibitor XIAP…………………………………………..30 3.3.2 XIAP:p19/p12-casp7 complex accumulation in estrogen-induced CASP3/DR T47D breast cancer cell through ERα signaling………...31 3.3.3 XIAP:p19/p12-casp7 complex could be the target of chemotherapies.32 (4) DISCUSSION…………………………………………………………………...34 REFERENCE……………………………………………………………………….38 FIGURE……………………………………………………………………………..54 SUPPLEMENTARY………………………………………………………………..83 APPENDIX………………………………………………………………………….84 | |
dc.language.iso | zh-TW | |
dc.title | 雌激素在表現雌激素受體的乳癌細胞中藉由抑制caspase-3表現而造成癌症惡化和抗藥性及雌激素造成caspase-3表現降低之分子機轉 | zh_TW |
dc.title | Estrogen stimulates cancer progression and chemoresistance through Caspase-3 down-regulation and the molecular mechanism underlying estrogen-induced CASP3/DR in ER-expressing breast cancer cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳瑞華(Ruey-Hwa Chen),蕭宏昇(Michael Hsiao) | |
dc.subject.keyword | 雌激素,雌激素受體,乳癌,抗藥性,激素替代療法, | zh_TW |
dc.subject.keyword | estrogen,estrogen receptor,breast cancer,drug resistance,hormone replacement therapy, | en |
dc.relation.page | 88 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-16 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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