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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82900完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華(Ruey-Hwa Chen) | |
| dc.contributor.author | Shu-Jou Chan | en |
| dc.contributor.author | 詹書柔 | zh_TW |
| dc.date.accessioned | 2022-11-25T08:02:08Z | - |
| dc.date.copyright | 2021-11-15 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-01 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82900 | - |
| dc.description.abstract | 長鏈非編碼RNA在癌症進展中具有至關重要的作用，但其功能機制尚未完全了解。根據我們實驗室先前研究發現Smyca的高度表現與多種癌症的不良預後和較高的病理分期有關，因此認為Smyca是致癌的長鏈非編碼RNA。另外，我們檢測了一群乳癌患者，發現基底樣亞型─三陰性乳癌患者的Smyca表現量顯著較高。由於 Smyca在間質樣乳癌細胞株和三陰性乳癌患者中高度表現，我們進一步探討Smyca是否促進上皮間質轉化（EMT）。我們在過表現Smyca的正常乳腺上皮細胞證實的確會促進EMT。在實驗室先前的RNAseq以及GSEA分析中發現Smyca所調控的基因特徵與TGF-β所調控的基因特徵具有高度相關。如同分析結果，我們證明了Smyca會促進TGF-β誘導的基因表現並且與TGF-β路徑形成正回饋調控。由於TGF-β訊息傳遞路徑在癌症進展中具有兩種截然不同的影響，我們想知道Smyca是否可活化其他促進腫瘤的路徑來抵銷TGF-β誘導的抑制生長作用。而重要的是，Myc基因特徵也與Smyca調控的基因特徵具高度相關性。我們進一步證實了Smyca不僅可透過增加Myc報告基因的活性，還可透過增加糖解和脂質代謝有關的Myc下游基因的轉錄作用。此外，我們的結果顯示Smyca可促進Myc募集到其目標基因以活化轉錄作用。有趣的是，我們發現Smyca透過促進Myc和TGF-β路徑來相反地調控CDK抑制因子p15/p21表現和腫瘤增殖。此外，我們證實了Smyca透過促進Myc和TGF-β路徑來協同提升糖解作用。最後，我們在動物實驗證實Smyca會促進乳癌轉移，而在無法和Smad結合的Smyca突變細胞株則會顯著抑制此轉移現象。此外，我們證明了Smyca knockdown可有效增強Doxorubicin的抗腫瘤作用，最終幾乎完全抑制腫瘤生長。因此，我們的研究揭示了Smyca透過活化TGF-β和Myc路徑在促進腫瘤進程中的作用，並顯示Smyca有望作為乳癌的標靶基因。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T08:02:08Z (GMT). No. of bitstreams: 1 U0001-3007202115572100.pdf: 6286691 bytes, checksum: e2174df90822dde4b1e20cd00acc585b (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 口試委員會審定書 i 誌 謝 ii 中文摘要 iii Abstract iv Contents vi List of Figures ix I. Introduction 1 1. Hallmarks of cancer 1 1.1 Overview 1 1.2 Metabolic reprogramming in cancer cells 3 1.3 Invasion-metastasis cascade 4 2. TGF-β pathway 6 2.1 Mechanism of TGF-β pathway 6 2.2 The role of TGF-β pathway in cancer progression 7 2.2.1 The tumor suppressive effects of TGF-β 7 2.2.2 The tumor promoting effects of TGF-β 8 3. Myc pathway 9 3.1 Myc functions as a transcription factor 9 3.2 Myc regulation in normal and cancer cells 9 3.3 The oncogenic functions of Myc 10 3.3.1 Overview 10 3.3.2 Metabolism 11 3.3.3 Targeting Myc-regulated metabolic pathway in cancer therapy 12 4. Long non-coding RNAs 13 4.1 Characteristics and molecular mechanism 13 4.2 LncRNAs in cancer 14 4.3 LncRNAs in TGF-β pathway 15 4.4 LncRNAs in Myc pathway 16 5. Smyca 17 II. Materials and Methods 19 Cell culture and transfection 19 Plasmids 19 Human specimens 19 Lentiviral transduction 20 Western blot 20 RT-qPCR 20 Luciferase reporter assay 21 Chromatin immunoprecipitation (ChIP) assay 21 RNA interference 22 BrdU cell proliferation assay 22 Measurement of glucose and lactate levels 22 Animal studies 23 Statistical analysis 23 III. Results 24 Smyca high expression correlates with higher malignant subtype of breast cancer. 24 Overexpression of Smyca in M10 cells promotes epithelial-mesenchymal transition. 24 Smyca serves as a positive regulator of TGF-β signaling. 25 Smyca forms a positive feedback loop with TGF-β signaling. 25 Smyca upregulated Myc pathway in transcriptional level. 26 Smyca-induced activation of Myc pathway antagonizes the growth inhibitory effect elicited by its activation of TGF-β pathway. 27 Smyca coordinates TGF-β and Myc pathways to synergize glycolysis. 28 Smyca promotes breast cancer metastasis via its Smad-binding region. 29 Smyca knockdown enhances the anti-tumor effect of Doxorubicin. 30 IV. Discussion 31 V. References 36 VI. Figures 48 VII. Appendix 62 Appendix 1 Primers used in this study 62 Appendix 2 GSEA hallmark analysis for the correlation of Smyca-induced gene signature with the indicated signatures. 64 | |
| dc.language.iso | en | |
| dc.subject | 腫瘤進程 | zh_TW |
| dc.subject | 上皮間質轉化/癌症轉移 | zh_TW |
| dc.subject | TGF-β | zh_TW |
| dc.subject | Myc | zh_TW |
| dc.subject | Smyca | zh_TW |
| dc.subject | 長鏈非編碼RNA | zh_TW |
| dc.subject | 糖解作用 | zh_TW |
| dc.subject | lncRNA | en |
| dc.subject | glycolysis | en |
| dc.subject | Myc | en |
| dc.subject | TGF-β | en |
| dc.subject | EMT/metastasis | en |
| dc.subject | tumor progression | en |
| dc.title | 長鏈非編碼RNA Smyca協同調控TGF-β和Myc路徑以促進腫瘤惡性化 | zh_TW |
| dc.title | The LncRNA Smyca Coordinates TGF-β and Myc Pathways to Promote Tumor Malignancies | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 袁維謙(Hsin-Tsai Liu),李育儒(Chih-Yang Tseng) | |
| dc.subject.keyword | 長鏈非編碼RNA,Smyca,腫瘤進程,上皮間質轉化/癌症轉移,TGF-β,Myc,糖解作用, | zh_TW |
| dc.subject.keyword | lncRNA,tumor progression,EMT/metastasis,TGF-β,Myc,glycolysis, | en |
| dc.relation.page | 64 | |
| dc.identifier.doi | 10.6342/NTU202101937 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-08-02 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-08-01 | - |
| 顯示於系所單位： | 生化科學研究所 | |
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