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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賴亮全(Liang-Chuan Lai) | |
| dc.contributor.author | Kuan-Yi Lee | en |
| dc.contributor.author | 李冠儀 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:23:50Z | - |
| dc.date.available | 2021-11-08 | |
| dc.date.available | 2022-11-24T03:23:50Z | - |
| dc.date.copyright | 2021-11-08 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-09-08 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80962 | - |
| dc.description.abstract | "癌症是目前發生率、死亡率皆高，且容易預後不良的疾病，而其中乳癌又為世界上盛行率最高的癌症之一。癌症的發生與腫瘤抑制基因(tumor suppressor gene)及致癌基因(oncogene)的突變有關，而近期有許多報導指出非編碼核糖核酸(non-coding RNAs)如：環形核糖核酸(circular RNAs, circRNAs)，在癌細胞的分子調控路徑和機制中扮演著腫瘤抑制或是致癌基因的角色，進而影響細胞功能以及癌症的進程。此外，在癌症發展的過程中腫瘤容易形成缺氧的微環境，而缺氧微環境會導致癌細胞變得更加惡性且增加治療的抗性。然而，環狀核糖核酸在乳癌中的潛在生物學功能和機制仍不清楚。因此，本篇研究假設在缺氧癌細胞中表現量下降的環形核糖核酸可能具有腫瘤抑制的特性，目的是想從中找到一個扮演抑癌角色的環形核糖核酸，並研究其在乳癌細胞中的調控機制。首先，我們從先前實驗室的乳癌細胞次世代定序(next generation sequencing)資料中篩選出缺氧環境下表現量顯著下降的環狀核糖核酸circAAGAB，接著確認其環狀構造，並驗證在缺氧環境中的不同乳癌細胞株間表現量皆顯著下降。我們發現circAAGAB大部分位於細胞質中，且會吸附及抑制微小核糖核酸(micro RNA, miRNA) miR-378h，並上調其下游基因KIAA1522和JADE3的表現量。此外，也發現circAAGAB和FUS有直接的交互作用，並會促進circAAGAB的穩定性。接著透過Affymetrix微陣列晶片(microarray)發現circAAGAB會參與p38 MAPK訊息傳遞路徑，細胞實驗驗證後也發現過表達circAAGAB會抑制乳癌細胞的群落形成、細胞爬行及侵襲能力，且增加乳癌細胞的輻射敏感性。由以上結果顯示circAAGAB為一缺氧下調的腫瘤抑制非編碼核醣核酸，在細胞質中會抑制miR-378h而上調其下游KIAA1522及JADE3表現量，另和FUS結合增加穩定性，也會透過p38 MAPK訊息傳遞路徑抑制細胞惡性，並增加輻射敏感性。此研究或許能幫助乳癌治療的發展能更進一步。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:23:50Z (GMT). No. of bitstreams: 1 U0001-0809202120190100.pdf: 2183120 bytes, checksum: a691abf02f8dbff90f483ca361d66961 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "致謝...I 摘要...II Abstract...IV List of Tables...VIII List of Figures...IX Chapter 1 Introduction...1 1.1 Molecular mechanism influences the occurrence of cancer and tumor progression...1 1.2 Circular RNAs are involved in modulating cell functions in cancer...2 1.3 Hypoxic tumor microenvironment promotes tumor malignancy and therapy resistance...4 1.4 The aim hypothesis of this study...6 Chapter 2 Materials and Methods...7 2.1 Cell culture...7 2.2 Plasmid construction, RNA interference and microRNA over-expressing...7 2.3 Genomic DNA extraction, RNA isolation, reverse transcription and quantitative RT-PCR...8 2.4 Western blotting...9 2.5 RNase R treatment...10 2.6 Actinomycin D treatment...10 2.7 Ionizing radiation treatment...11 2.8 Nuclear-cytoplasmic fractionation...11 2.9 RNA pull-down assay...12 2.10 Luciferase reporter assay...13 2.11 Microarray analysis...13 2.12 BrdU and Immunofluorescence assay...14 2.13 MTT assay...15 2.14 Colony formation assay...15 2.15 Cell migration and invasion assay...15 2.16 Cell apoptosis and cell cycle analysis...16 2.17 Statistical analysis...17 Chapter 3 Results...18 3.1 A novel circular RNA, circAAGAB was downregulated under different oxygen concentrations in breast cancer cells...18 3.2 CircAAGAB acted as a sponge for miR-378h and inhibited its effect on target genes...20 3.3 RNA binding protein FUS increased the stability of circAAGAB via direct binding...22 3.4 CircAAGAB was involved in p38 MAPK signaling pathway and apoptosis-related pathways...24 3.5 CircAAGAB reduced colony formation, cell migration, invasion and epithelial–mesenchymal transition in MDA-MB-231 cells...25 3.6 CircAAGAB increased radiosensitivity in MDA-MB-231 cells...26 Chapter 4 Discussion...29 4.1 CircAAGAB acted as a sponge for miR-378h to up-regulate expression levels of KIAA1522 and JADE3...29 4.2 FUS directly bound circAAGAB and improved its stability...31 4.3 CircAAGAB inhibited cell colony formation, migration and invasion in breast cancer cells through p38 MAPK signaling pathway...32 4.4 Increasing radiosensitivity caused by circAAGAB might involve in p38 MAPK signaling pathway in breast cancer cells...34 4.5 Limitations of this study...36 4.6 Conclusion...38 Tables...39 Figures...46 References...67" | |
| dc.language.iso | en | |
| dc.subject | 缺氧 | zh_TW |
| dc.subject | circAAGAB | zh_TW |
| dc.subject | 輻射敏感性 | zh_TW |
| dc.subject | 乳癌 | zh_TW |
| dc.subject | 細胞功能 | zh_TW |
| dc.subject | 腫瘤抑制基因 | zh_TW |
| dc.subject | breast cancer | en |
| dc.subject | radiosensitivity | en |
| dc.subject | cell function | en |
| dc.subject | hypoxia | en |
| dc.subject | circAAGAB | en |
| dc.subject | tumor suppressor gene | en |
| dc.title | 探討缺氧反應之環形核糖核酸circAAGAB在乳癌細胞中之腫瘤抑制功能與輻射敏感性 | zh_TW |
| dc.title | Investigation of the Tumor-Suppressing Roles and Radiosensitivity of Hypoxia-Responsive Circular RNA circAAGAB in Breast Cancer Cells | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蔡孟勳(Hsin-Tsai Liu),楊鎧鍵(Chih-Yang Tseng),佘玉萍,蕭貴陽 | |
| dc.subject.keyword | 乳癌,腫瘤抑制基因,circAAGAB,缺氧,細胞功能,輻射敏感性, | zh_TW |
| dc.subject.keyword | breast cancer,tumor suppressor gene,circAAGAB,hypoxia,cell function,radiosensitivity, | en |
| dc.relation.page | 71 | |
| dc.identifier.doi | 10.6342/NTU202103068 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-09-09 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| 顯示於系所單位： | 生理學科所 | |
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