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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99677完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭靜穎 | zh_TW |
| dc.contributor.advisor | Ching-Ying Kuo | en |
| dc.contributor.author | 吳宜臻 | zh_TW |
| dc.contributor.author | Yi-Zhen Wu | en |
| dc.date.accessioned | 2025-09-17T16:20:53Z | - |
| dc.date.available | 2025-09-18 | - |
| dc.date.copyright | 2025-09-17 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-06 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99677 | - |
| dc.description.abstract | 當腫瘤在生長過程中遭遇到壓力時，癌細胞會啟動壓力反應並透過調控轉錄路徑來調控細胞的行為，這樣的機制使得癌細胞能發展出表型可塑性(phenotypic plasticity)以因應壓力。在癌症進展過程中，癌細胞常因腫瘤微環境中營養供應不足而遭受代謝壓力。然而，目前對於癌細胞調控代謝壓力反應及代謝壓力如何影響表型可塑性的機制仍未完全釐清。本研究旨在探討乳癌細胞如何因應代謝壓力，並會聚焦於長鏈非編碼核糖核酸UBA6-AS1與轉錄因子EGR1在營養缺乏情況下所扮演的角色。
第一部分的研究主要是在探討UBA6-AS1在胺基酸缺乏下的功能。研究結果顯示，整合性壓力反應(integrated stress response)的核心路徑GCN2/ATF4會於麩醯胺酸(glutamine)和精胺酸(arginine)缺乏時上調UBA6-AS1的表現。而UBA6-AS1的上調會進一步促進PARP1的表現，進而增加細胞在代謝壓力下的存活能力。然而，UBA6-AS1的上調雖然促進了細胞的存活，卻也同時抑制了細胞的遷移能力，顯示其在代謝壓力下會調控細胞在生長與轉移之間的平衡(trade-off)。 第二部分的研究主要是在研究EGR1在葡萄糖缺乏下的表現與功能。研究結果顯示EGR1在代謝壓力之下的表現量會透過ROS/p38/Elk-1以及GCN2/ATF4兩條路徑被誘導。EGR1被上調後會抑制HERPUD1的表現，並且會部分抑制由IRE1所介導的未折疊蛋白反應(unfolded protein response)。這樣的機制能避免未折疊蛋白反應過度或延長活化，進而協助維持內質網恆定以及促進癌細胞於葡萄糖缺乏下的表型可塑性。不同的功能性試驗顯示EGR1除了能促進細胞在代謝壓力下的存活外，也會促進細胞對於失巢凋亡(anoikis resistance)的抗性，並同時抑制糖解作用與粒線體氧化磷酸化。由這些結果可以推論出在代謝壓力下EGR1能夠多面向地調控細胞的行為。 基於EGR1對代謝壓力的高度敏感性與快速反應性，本研究建立了一套以EGR1啟動子驅動Cre蛋白表現的報導系統。該系統可以在EGR1被誘發時將細胞由紅色螢光不可逆地轉換為綠色螢光，使曾經經歷代謝壓力的細胞能被追蹤其細胞命運與行為的變化，並作為一個可用來長期觀察細胞應對代謝壓力之過程及其轉移能力變化的工具。 總結來說，本研究發現乳癌細胞會分別透過UBA6-AS1以及EGR1調控代謝壓力反應並促進細胞於代謝壓力下的表型可塑性。這些結果顯示出癌細胞對不同營養缺乏所導致的代謝壓力調控具高度的特異性及複雜性，並為未來發展針對代謝壓力的乳癌治療策略提供新的標的與方向。 | zh_TW |
| dc.description.abstract | To adapt and survive from stress, cancer cells develop phenotypic plasticity through activating stress response which is mediated by diverse transcriptional programs to modulate phenotypic behaviors. During cancer progression, cancer cells are frequently exposed to metabolic stress due to insufficient nutrient supply in the tumor microenvironment. Nonetheless, the regulatory mechanism of metabolic stress response remains incompletely understood. This thesis would investigate how breast cancer cells respond to metabolic stress, which particularly focused on the role of long non-coding RNA UBA6-AS1 and transcription factor EGR1 under nutrient deprivation conditions.
In the first part of the study, the role of UBA6-AS1 was investigated during amino acid deprivation. GCN2/ATF4 signaling axis, the core component of the integrated stress response, transcriptionally upregulated UBA6-AS1 upon glutamine and arginine starvation. The upregulation of UBA6-AS1 further enhanced the expression of PARP1, which promoted cell survival under stress conditions. Although UBA6-AS1 promoted cell survival under metabolic stress, it simultaneously suppressed the migratory ability of breast cancer cells, suggesting UBA6-AS1 mediated the trade-off between survival and metastasis in response to metabolic stress. In the second part, the role of transcription factor EGR1 under glucose deprivation was examined. EGR1 was induced by both ROS/p38/Elk-1 and GCN2/ATF4 signaling pathways upon glucose deprivation. After induction, EGR1 was found to suppress HERPUD1 expression and partially inhibited IRE1-mediated unfolded protein response (UPR) signaling, which prevented prolonged or excessive UPR activation, thereby maintaining ER homeostasis and promoting phenotypic plasticity under glucose starvation. EGR1 was demonstrated to regulate phenotypic plasticity through enhancing anoikis resistance and cell survival, whereas concurrently suppressing both glycolysis and oxidative phosphorylation, implying the multifaceted regulation of EGR1 on cell behavior upon metabolic stress. Based on the rapid responsiveness and sensitivity of EGR1 on metabolic stress, an EGR1 promoter-driven Cre reporter system was developed to visualize and trace the metabolic stress-experiencing cells. This reporter system irreversibly converted cells from red to green fluorescence upon EGR1 activation, and provided a lineage-tracing strategy to monitor how metabolic stress-exposed cells behaved or metastasized over time. Collectively, these findings revealed that breast cancer cells fine-tuned stress response signaling to regulate phenotypic plasticity under metabolic stress through UBA6-AS1 and EGR1. These mechanisms highlighted the complexity and specificity of cancer cell adaptation to metabolic stress induced by the deficiency of distinct nutrient, which provided the opportunity to develop future therapeutic strategies targeting metabolic vulnerabilities in breast cancer. | en |
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| dc.description.provenance | Made available in DSpace on 2025-09-17T16:20:53Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 誌謝 i
摘要 ii Abstract iv List of Abbreviations vi List of Figures xvi Chapter I. Introduction 1 I.1 Breast Cancer 1 I.1.1 Causes and Risk Factor of Breast Cancer 1 I.1.2 Classification of Breast Cancer 2 I.1.3 Staging of Breast Cancer 3 I.1.4 Breast Cancer Metastasis 3 I.1.5 Treatments for Breast Cancer 5 I.2 Metabolic Stress in Cancer 6 I.3 Stress Response 7 I.3.1 Hypoxic Stress Response 8 I.3.2 Unfolded Protein Response 8 I.3.3 Integrated Stress Response 11 I.4 Phenotypic Plasticity 12 I.5 Long non-coding RNA 12 I.5.1 Classification of lncRNAs 13 1.5.2 Function of lncRNAs 13 I.5.3 Role of lncRNAs in Cancer 15 I.5.4 The Regulation of lncRNAs on Stress Response 16 I.6 Early Growth Response Family 17 I.6.1 Introduction of EGR1 18 I.6.2 Function of EGR1 19 I.6.3 EGR1 and Stress Response 19 I.6.4 EGR1 and Cancer 20 I.6.5 Post-translational modifications of EGR1 21 Chapter II. Rationale and Purpose 23 Chapter III. Materials and Methods 24 III.1 Cell culture and reagents 24 III.2 Chemicals 24 III.3 Animal study 25 III.4 RNA isolation, cDNA synthesis, and qPCR 26 III.5 Breast cancer tissue microarray 27 III.6 SDS-PAGE and Western Blotting 27 III.7 Cell viability and proliferation assay 29 III.8 Anoikis resistance assay 29 III.9 3D spheroid formation 30 III.10 siRNA transfection 30 III.11 Lentiviral production and transduction 30 III.12 Mitochondrial function analysis 31 III.13 Transwell migration assay 31 III.14 RNA-Seq and dataset analysis 32 III.15 Subcellular fractionation 32 III.16 Polymerase chain reaction 33 III.17 Site-directed mutagenesis 34 III.18 Chromatin immunoprecipitation (ChIP)-Seq analysis 34 III.19 Immunoprecipitation 34 III.20 Transcription factor binding site prediction 35 III.21 Immunofluorescence staining and imaging 35 III.22 Competition assay 35 III.23 Seahorse Bioenergetic Analysis 36 III.24 In vitro dephosphorylation assay 36 III.25 Organoid culture 37 III.26 Statistical analysis 37 Chapter IV. Results-part I 38 IV.1 UBA6-AS1 was upregulated in tumor and may be involved in the regulation of integrated stress response 38 IV.2 UBA6-AS1 was upregulated in TNBC cells upon metabolic stress and ER stress 39 IV.3 Characterization of the localization and the transcript variant of UBA6-AS1 40 IV.4 UBA6-AS1 promoted BC cell growth under metabolic stress and ER stress 42 IV.5 GCN2/ATF4-mediated ISR was responsible for the upregulation of UBA6-AS1 upon amino acid deprivation 43 IV.6 PARP1 was identified as the downstream target of UBA6-AS1 and regulated cell survival upon amino acid deprivation 45 IV.7 Conclusion 47 Chapter V. Results-part II 48 V.1 Metabolic stress induced EGR1 expression through ROS/p38/Elk-1 axis in BC cells 48 V.2 EGR1 drove metabolic stress adaptation and breast cancer progression 50 V.3 EGR1 rendered cell metabolism more quiescent and promoted migratory ability upon glucose deprivation 51 V.4 ChIP-Seq analysis indicated that EGR1 might involve in the regulation of several metastatic processes 52 V.5 EGR1 suppressed IRE1ɑ-mediated unfolded protein response upon metabolic stress 54 V.6 EGR1 was phosphorylated at Thr-391 residue under metabolic stress 54 V.7 Establishing and validating EGR1-based fate-mapping reporter system 57 V.8 Conclusion 59 Chapter VI. Discussion 60 VI.1 Multifaceted regulation of metabolic stress response on cell behavior promotes the development of phenotypic plasticity 60 VI.2 PARP1 may be a crucial effector in metabolic stress response 60 VI.3 Context-dependent regulation of GCN2/ATF4 axis on stress response upon the deprivation of distinct amino acid 61 VI.4 Balancing energy conservation and stress resolution through EGR1 62 VI.5 EGR1 may coordinate transcription and translation networks to prevent prolonged IRE1-mediated UPR 63 VI.6 EGR1-based irreversible reporter offers a powerful approach to dissect the underlying mechanism of metabolic stress response in tumor 65 VI.7 Importance of UPR and ISR during cancer progression and treatment 65 VI.8 Targeting metabolic vulnerability for breast cancer treatment 66 Chapter VII. Figures 68 Chapter VIII. References 113 Chapter IX. Appendix 130 Appendix 1. EGR1 was induced in various breast cancer cell lines upon glucose starvation. 130 Appendix 2. EGR1 was transcriptionally upregulated upon metabolic stress. 131 Appendix 3. EGR1 was induced in nucleus and in the core region of tumor spheroid. 132 Appendix 4. EGR1 was induced by ROS/p38 axis under metabolic stress. 133 Appendix 5. EGR1 suppressed cancer cell growth under nutrient sufficient condition. 134 Appendix 6. EGR1 was induced along with tumor growth to promote progression. 136 Appendix 7. Point mutation on potential EGR1 SUMOylated sites did not affect its protein pattern and localization. 137 Appendix 8. T391A point mutation did not alter EGR1 subcellular localization but abrogated DNA binding affinity of EGR1. 138 Appendix 9. EGR1 phosphorylation was abrogated by GCN2 inhibitor under metabolic stress. 139 Appendix 10. Verification of the EGR1-based metabolic stress reporter system. 140 | - |
| dc.language.iso | en | - |
| dc.subject | 代謝壓力 | zh_TW |
| dc.subject | 整合性壓力反應 | zh_TW |
| dc.subject | 未折疊蛋白反應 | zh_TW |
| dc.subject | 乳癌 | zh_TW |
| dc.subject | EGR1 | zh_TW |
| dc.subject | UBA6-AS1 | zh_TW |
| dc.subject | 壓力反應 | zh_TW |
| dc.subject | unfolded protein response | en |
| dc.subject | breast cancer | en |
| dc.subject | metabolic stress | en |
| dc.subject | UBA6-AS1 | en |
| dc.subject | integrated stress response | en |
| dc.subject | EGR1 | en |
| dc.title | 探討乳癌進程中透過表型可塑性適應代謝壓力之調控機制 | zh_TW |
| dc.title | Investigating the Regulatory Mechanisms of Phenotypic Plasticity in Response to Metabolic Stress During Breast Cancer Progression | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 安康 | zh_TW |
| dc.contributor.coadvisor | David K. Ann | en |
| dc.contributor.oralexamcommittee | 楊雅倩;莊健盈;蘇剛毅;林能裕 | zh_TW |
| dc.contributor.oralexamcommittee | Ya-Chien Yang;Jian-Ying Chuang;Kang-Yi Su;Neng-Yu Lin | en |
| dc.subject.keyword | 乳癌,代謝壓力,UBA6-AS1,EGR1,壓力反應,整合性壓力反應,未折疊蛋白反應, | zh_TW |
| dc.subject.keyword | breast cancer,metabolic stress,UBA6-AS1,EGR1,integrated stress response,unfolded protein response, | en |
| dc.relation.page | 140 | - |
| dc.identifier.doi | 10.6342/NTU202503414 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-08-06 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學系 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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