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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 黃敏銓(Min-Chuan Huang) | |
dc.contributor.author | Mei-Chun Lin | en |
dc.contributor.author | 林玫君 | zh_TW |
dc.date.accessioned | 2021-06-16T09:27:43Z | - |
dc.date.available | 2017-09-12 | |
dc.date.copyright | 2017-09-12 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-05-08 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59554 | - |
dc.description.abstract | GATA3對於T細胞及許多人體器官的分化佔有重要的地位,但是在人類癌症的角色尚未被研究。本研究發現,GATA3在頭頸部鱗狀上皮癌有過量的表現,並且和病人較差的存活率及臨床預後因子有關。在小鼠實驗中,GATA3的表現會促進腫瘤生長及轉移。在頭頸癌及黑色素瘤細胞中,GATA3會促進細胞爬行及侵犯,在低氧環境中,這些惡行表型會更明顯。機轉上,GATA3和HIF-1α 有相互作用,並藉此競爭掉RACK1,此種作用,會使HIF-1α不被蛋白酶體代謝而更穩定。GATA3所造成的細胞侵入,可以藉由減少HIF-1α的表現或是過度表現N-HIF-1α (第1-401胺基酸) 而被抑制。這些研究指出,GATA3除了作為轉錄因子,也可藉由調控其HIF-1α穩定性,進而影響癌細胞的侵入。 | zh_TW |
dc.description.abstract | GATA3 is pivotal in maturation and differentiation of T helper 2 cells as well as many human organs. However, the clinical significance and roles of transcription factor GATA3 in human cancers remain elusive. Here, we report that GATA3 is overexpressed in head and neck squamous cell carcinoma (HNSCC) compared with adjacent non-tumor mucosa. GATA3 expression positively correlates with metastasis and is an independent predictor for poor disease-free survival. In murine models, GATA3 promotes tumor growth and metastasis. In HNSCC cells, GATA3 enhances migration and invasion under normoxia and these invasive behaviors are further increased by hypoxia. Mechanistically, GATA3 physically interacts with and stabilizes hypoxia inducible factor (HIF)-1α by competing activated protein kinase C 1 (RACK1) binding, hence regulating HIF-1 target genes under hypoxia. Moreover, the GATA3-mediated invasiveness can be significantly reversed by HIF-1α knockdown or expression of the N-terminal part of HIF-1α (aa 1-401), suggesting a critical role of HIF-1α in the underlying mechanism. These findings demonstrate a novel function of GATA3 as a HIF-1α regulator to enhance cancer invasiveness and support the GATA3/HIF-1α axis as a new therapeutic target for HNSCC treatment. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T09:27:43Z (GMT). No. of bitstreams: 1 ntu-106-D03446002-1.pdf: 3644231 bytes, checksum: 87a9562933df3373470a253d76f5d31a (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 致謝 5
Abstract 7 Chapter 1. Introduction 8 Chapter 2. Materials and Methods 11 2.1 Tissue samples 11 2.2 Immunohistochemistry 11 2.3 Plasmid construction 11 2.4 Cell cultures and transfection 12 2.5 RNA extraction and real-time RT-PCR 12 2.6 Transwell migration assay and Matrigel invasion assay 13 2.7 Co-immunoprecipitation and Western blot analysis. 13 2.8 GST pull-down assays. 14 2.9 Immunofluorescence confocal microscopy. 15 2.10 Chromatin immunoprecipitation assays (ChIP) 15 2.11 Animals 15 2.12 Differential expression analysis and functional analysis 16 2.13 Sphere formation assay 17 2.14 Apoptosis assay 17 2.15 Statistics 18 Chapter 3. Results 19 3.1 GATA3 is overexpressed in HNSCC and predicts poor prognosis 19 3.2 GATA3 promotes tumor cell invasiveness in vitro 19 3.3 GATA3 promotes tumor invasiveness in vivo 20 3.4 GATA3 expression increases HIF-1α protein level 21 3.5 Positive correlation of GATA3 and HIF-1α expression in clinical samples 22 3.6 GATA3 physically interacts with HIF-1α 22 3.7 GATA3 regulates the expression of HIF-1 target genes under hypoxia 24 3.8 GATA3-induced invasive behaviors are reversed by HIF-1α knockdown or N-HIF-1α expression 24 3.9 The enriched functions underlying GATA3/HIF-1α axis under hypoxia 25 3.10 GATA3 enhances cell viability under serum-deprived conditions 26 3.11 Knockdown of GATA3 causes G1 arrest and induces apoptosis in FaDu cells 26 3.12 GATA3 enhances sphere formation in SAS cells 26 Chapter 4. Discussion 28 Chapter 5. References 32 Figures and figure legends 38 Tables 55 | |
dc.language.iso | en | |
dc.title | 轉譯因子GATA3在頭頸癌中的角色 | zh_TW |
dc.title | The role of transcription factor GATA3 in head and neck squamous cell carcinoma | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 婁培人(Pei-Jen Lou) | |
dc.contributor.oralexamcommittee | 李明學(Ming-Shyue Lee),王淑慧(Shu-Huei Wang),阮雪芬(Hsueh-Fen Juan),林敬哲(Jing-Jer Lin) | |
dc.subject.keyword | 頭頸部鱗狀上皮癌,GATA3,缺氧,HIF-1α, | zh_TW |
dc.subject.keyword | head and neck squamous cell carcinoma (HNSCC),GATA3,hypoxia,HIF-1α, | en |
dc.relation.page | 64 | |
dc.identifier.doi | 10.6342/NTU201700793 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-05-10 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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