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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95075完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華 | zh_TW |
| dc.contributor.advisor | Ruey-Hwa Chen | en |
| dc.contributor.author | 張耕豪 | zh_TW |
| dc.contributor.author | Keng-Hao Chang | en |
| dc.date.accessioned | 2024-08-27T16:15:03Z | - |
| dc.date.available | 2024-08-28 | - |
| dc.date.copyright | 2024-08-27 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-07-03 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95075 | - |
| dc.description.abstract | 三陰性乳癌(TNBC)是在乳癌中最具侵略性的類型。由於缺乏有效的標靶治療，其治療選擇主要局限於化療。我們實驗室先前的研究確認了Smyca作為在TNBC中高度表達的長鏈非編碼RNA，它協調TGF-β和MYC路徑以促進多種惡性特徵，包括上皮間質轉化(EMT)、幹细胞特性、代謝重整和化療抗藥性。在本篇研究中，我們發現了抑制Smyca和PARP抑制劑的合成致死性。機制上來說，Smyca和FoxM1 相互作用並促進了一群 FoxM1目標基因的表達，以影響同源重组（HR）的進行。因此，缺乏Smyca損害了HR進行並增加TNBC细胞對基因毒性劑和PARP抑制劑的敏感性。在這種條件下，Smyca的缺失還誘導了micronuclei並活化cGAS/STING先天免疫路徑，吸引CD3+ T细胞向TNBC細胞移動，表明了抗腫瘤免疫反應的誘導。使用gapmer抗寡寡核苷酸（ASO）靶向 Smyca增強了基因毒性劑和PARPi在TNBC小鼠模型中的抗腫瘤效果。我們的研究提供了將靶向Smyca與化療或PARP抑制劑结合治療TNBC之策略的潜力。 | zh_TW |
| dc.description.abstract | Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Because of lacking effective targeted therapy, its treatment options are mainly limited to chemotherapy. Previous study in our laboratory identified Smyca as a lncRNA highly expressed in TNBC, which coordinates TGF-β and MYC pathways to promote multiple malignant features TNBC including EMT, stemness, metabolic reprogramming, and chemoresistance. In this thesis, we discovered the synthetic lethality of Smyca inhibition and PARP inhibitor. Mechanistically. Smyca interacts with FoxM1 and promotes the expression of a set of FoxM1 targets acting on the homologous recombination (HR) process. Smyca depletion impairs HR and sensitizes TNBC cells to genotoxic agent and PARP inhibitor. Smyca depletion in this condition also induces micronuclei and activates cGAS/STING innate immunity pathway to attract CD3+ T cells toward TNBC cells, suggesting the induction of anti-tumor immune responses. Targeting Smyca using gapmer antisense oligonucleotides (ASO) potentiates the anti-tumor effect of genotoxic agent and PARPi in TNBC mouse models. Our study provides the potential of targeting Smyca in combination with chemotherapy or PARP inhibitor as a strategy for TNBC treatment. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-27T16:15:03Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-27T16:15:03Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 中文摘要 iii Abstract iv Table of Contents v I. Introductions 1 1. Triple Negative Breast Cancer 1 1.1 Overview of breast cancer 1 1.2 Target therapies in breast cancer 2 1.3 Treatments for TNBC 4 2. cGAS/STING pathway 6 2.1. Mechanism of cGAS/STING pathway 6 2.2. The regulation of cGAS/STING pathway in cancer 7 2.3. Immunotherapy and cGAS/STING pathway 9 3. DNA repair 11 3.1. Overview of DNA repair 11 3.2. DNA repairs and cancer therapies 17 4. LncRNA 20 4.1. Overview of lncRNA 20 4.2. LncRNA and cancer 22 4.3. LncRNA Smyca 23 II. Materials and Methods 26 III. Results 35 Smyca knockdown sensitizes TNBC cells to genotoxic agent and enables synthetic lethality to PARPi 35 Smyca knockdown impairs the repair of DNA double-strand breaks 36 Smyca promotes HR directly 37 Smyca promotes FoxM1 activity and the expression of FoxM1-regulated repair genes 38 Smyca knockdown induces micronuclei formation in basal and drug-treated conditions 40 Smyca knockdown in drug-treated TNBC cells enhances cGAS/STING pathway to induce type I interferon responses 41 Smyca knockdown in drug-treated TNBC cells enhances the chemotactic migration of CD3+ T cells towards tumor cells 42 Targeting Smyca combining PARPi or cisplatin treatment inhibits tumor growth in TNBC mouse models 43 IV. Discussions 45 V. References 50 VI. Figures 66 VII. Appendix 91 | - |
| dc.language.iso | en | - |
| dc.subject | 長鏈非編碼RNA | zh_TW |
| dc.subject | Smyca | zh_TW |
| dc.subject | 三陰性乳癌 | zh_TW |
| dc.subject | 合成致死性 | zh_TW |
| dc.subject | PARP抑制劑 | zh_TW |
| dc.subject | cGAS/STING路徑 | zh_TW |
| dc.subject | 同源重組 | zh_TW |
| dc.subject | Smyca | en |
| dc.subject | homologous recombination | en |
| dc.subject | cGAS/STING pathway | en |
| dc.subject | synthetic lethality | en |
| dc.subject | PARPi | en |
| dc.subject | TNBC | en |
| dc.subject | LncRNA | en |
| dc.title | 長鏈非編碼RNA Smyca促進由FoxM1調控之同源重組以控制三陰性乳癌中的免疫逃脫及治療抗藥性 | zh_TW |
| dc.title | The LncRNA Smyca promotes FoxM1-mediated homologous recombination to control TNBC immune evasion and therapy resistance | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 徐立中;李育儒 | zh_TW |
| dc.contributor.oralexamcommittee | Li-Chung Hsu;Yu-Ru Lee | en |
| dc.subject.keyword | 長鏈非編碼RNA,Smyca,三陰性乳癌,合成致死性,PARP抑制劑,cGAS/STING路徑,同源重組, | zh_TW |
| dc.subject.keyword | LncRNA,Smyca,TNBC,PARPi,synthetic lethality,cGAS/STING pathway,homologous recombination, | en |
| dc.relation.page | 95 | - |
| dc.identifier.doi | 10.6342/NTU202401452 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2024-07-04 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 分子醫學研究所 | - |
| 顯示於系所單位： | 分子醫學研究所 | |
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