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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李財坤 | |
dc.contributor.author | Yen-Hsiu Yeh | en |
dc.contributor.author | 葉彥秀 | zh_TW |
dc.date.accessioned | 2021-06-16T08:14:22Z | - |
dc.date.available | 2017-02-25 | |
dc.date.copyright | 2014-02-25 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-02-13 | |
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'The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligase.' J Biol Chem 281(7): 3989-3994. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58416 | - |
dc.description.abstract | 2013年國人十大死因之首,惡性腫瘤(癌症),連續三十一年蟬聯冠軍。癌症已成為致死率最高的疾病,因此,全世界許多科學研究者致力於探討癌症發生與進程的可能分子機制。其中,慢性發炎(chronic inflammation)更是近年來,被許多分子及病理學證實,可藉由改變宿主的免疫機轉而影響癌化的進行。慢性發炎,有如缺氧微環境,除被認為是一關鍵癌化的微環境因素外,更是人體內的沉默殺手,可導致心臟病、腦中風等慢性疾病的生成。本論文探討不同的微環境的交互作用與對腫瘤進程的的影響分為兩部分:(一)干擾素刺激基因15(interferon-stimulated gene15,ISG15)和泛素(ubiquitin)結合路徑在缺氧和發炎所營造的發炎缺氧微環境(inflammatory hypoxia)扮演重要的角色。為了探究兩者癌症環境間的交互作用,我們研究ISG15對影響缺氧誘導因子(hypoxia- inducible factor-1α,HIF-1α)的活性影響。利用Interferon和模擬缺氧藥物desferoxamine的刺激,誘發ISG15和HIF-1α的產生,發現干擾素刺激基因15(ISG15)可藉由蛋白質後修飾作用來影響HIF-1α的功能性。探討其中的機制,我們發現HIF-1α不僅和ISG15有物理性的交互作用,也是同時亦是干擾素引發的蛋白質後修飾作用(ISGylation) 的受質蛋白 (Substrate),在多處區域有修飾點。過度表現ISG15瓦解HIF-1α和HIF-1β的偶合作用(dimerization)。緊接著,HIF-1α引發的基因表現和癌症生長也會被ISG15和ISGylation所弱化。綜合以上結果,一個全新的缺氧負回饋機制被我們提出,干擾素可透過對HIF-1α進行ISGylation達成對缺氧的微環境調節。(二)延續第一部分的發現,我們探討慢性發炎和癌症發生的相關性。多方的證據顯示,癌細胞可藉由駕馭訊息傳遞路徑在艱困微環境下適應生存。HIF-1α在匯集發炎和缺氧通往癌症的調控網域上扮演一個重要角色,因此HIF-1α在許多癌症都有過度表現的現象。利用抗病毒的interferon模擬慢性發炎環境,觀察到干擾素向上調控細胞中HIF-1α的表現。並探究背後機制及其生理意義。在769-P腎臟癌細胞中,我們發現HIF-1α路徑可被發炎干擾素所調控,而誘發的HIF-1α累積是透過PI3K/AKT/mTOR/GSK3β路徑。為了確認干擾素誘發HIF-1α產生的可能機制,一系列藥理學方法被應用來揭開其中所蘊含的調控機制。結果顯示,干擾素也藉由促進HIF-1α的轉譯作用增加其表現量。更重要的是,干擾素藉由誘發的HIF-1α來促進上皮細胞中胚轉化(epithelial-mesenchymal transition,EMT)和細胞侵襲性。同樣的,利用RNA interference干擾方式壓制干擾素所誘發之HIF-1α。綜合以上結果,干擾素在有些細胞可以促進缺氧誘導因子表現,並且透PI3K/AKT/mTOR/GSK3β路徑影響上皮細胞中胚轉化(epithelial-mesenchymal transition,EMT)的發生。此為第一次報導干擾素可經由誘發缺氧誘導因子累積,進而影響癌症發生,可提供臨床上,癌症治療策略使用的考慮因素。 | zh_TW |
dc.description.abstract | Because cancer has become the highest mortality among diseases, researchers around the world are committed to uncover the potential tumorigenic mechanisms and related intervention of concurring cancer. In recent years, inflammation has regarded as the enhancing characteristics of cancer hallmarks and been proven to contribute to tumor initiation and progression. Inflammation, like hypoxia microenvironment, is also a critical factor for a variety of diseases such as heart disease, stroke and diabetes. Here, we have investigated interactions between microenvironments and relation with cancer development. Thus, my study has divided into two major parts. [I] We found that ISG15 (interferon-stimulated gene 15) modulates hypoxia-inducible factor-1α (HIF-1α) functions. ISG15 conjugation (ISGylation) and ubiquitylation systems play critical roles in hypoxic inflammation. Interferon and hypoxia-mimetic desferoxamine were used to induce ISG15 and HIF-1α expression respectively and to study effects of ISG15 on the HIF-1α activity. We observed free-form HIF-1α is regulated by interferon, and expression of ISG15 is lower in the hypoxic state. Further mechanistic investigation reveals HIF-1α not only physically interacts with ISG15 but also is a substrate for ISGylation at multiple sites. Overexpression of ISG15 disrupted HIF-1α/HIF-1β dimerization and subsequently HIF-1α-induced gene expression and tumor growth in xenograft mouse models were attenuated by ISG15 and ISGylation expression. Based on the above results, we concluded and proposed a novel negative feedback mechanism of hypoxia where ISG15 regulates HIF-1α via ISGylation. [II] Accumulating evidence demonstrate that tumor cells highjack signaling pathways to exploit the machinery for tumor microenvironments and to adapt and help survival under stress environments. Among these regulatory networks, HIF-1α plays a crucial role linking hypoxia and inflammation to cancer, thus elevated expression of HIFs are often observed in tumors. Here, we have found that the HIF-1α pathway is modulated by the inflammatory cytokine IFN-α in 769-P renal cancer cell and our mechanistic study has determined the involvement of PI3K/AKT/mTOR/GSK3β pathways in the IFN-induced HIF-1α accumulation. HIF-1α expression was elevated in a time- and concentration-dependent manner by IFN-α and requires transcription. Moreover, cells were exposed to a serial of pharmacological inhibitors to investigate their effects on the IFN-mediated HIF-1α accumulation and revealing that the de novo synthesis is also involved in the IFN-induced HIF-1α. Importantly, IFN-α also triggers epithelial-to-mesenchymal transition (EMT) via up-regulation of HIF-1α as evident by the fact that IFN-α-induced EMT is attenuated by silencing of HIF-1α expression. To our knowledge, the above results demonstrate for the 1st report that IFN-α is a contributing factor for cancer development through modulating of HIF-1α expression and thus providing considerable strategy in clinical for tumor-therapy with IFN-α. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:14:22Z (GMT). No. of bitstreams: 1 ntu-103-D95445010-1.pdf: 5592579 bytes, checksum: a8d86b250e51f3f231e3addd0e62852e (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 封面 p1
Contents p2 中文摘要 p9 Abstract p11 Chapter One: Overall introduction on microenvironment and tumorigenesis p13 1. Hallmarks of cancer p14 1.1 Sustaining proliferative signaling p14 1.2 Evading growth suppressors p15 1.3 Resisting cell death p17 1.4 Enabling replicative immortality p18 1.5 Inducing angiogenesis p18 1.6 Activating invasion and metastasis p19 1.7 An enabling characteristics: genome instability and mutation p20 1.8 An enabling characteristics: Tumor-Promoting inflammation p21 1.9 An emerging hallmark: Reprogramming energy metabolism p22 1.10 An emerging hallmark: Evading immune destruction p23 2 Tumor microenvironments p24 2.1 Hypoxia and tumorigenesis p25 2.2 Hypoxic and acidic environments p26 2.3 Inflammation and tumorigenesis p27 2.4 Epithelial-mesenchymal transition (EMT) p31 3. Post-translational modifications: ISGyalation and ubiquitinylation p34 3.1 The ISG15 conjugation (ISGylation) pathway p34 3.1.1 ISG15 p36 3.1.2 UBE1L/Uba7, the E1 activating enzyme p37 3.1.3 UbcH8/UBE2L6 E2 conjugating enzyme p38 3.1.4 ISGyaltion E3 ligases: Herc5, EFP/TRIM25 and HHARI p39 3.1.5 ISG15 protease UBP43 - a deISGylase p40 3.2 ISG15, ISGylation and cancer p42 3.3 Ubiquitinylation p45 4. The interferon response in inflammation p46 4.1 The interferon responses p46 4.1.1 Canonical pathway activated by IFN-α via JAK-Stat1 pathway p48 4.1.2 Auxilliary pathway activated by IFN-α: PI3K/AKT, mTOR and MAPK/P38 pathways p48 4.2 HIF-1α is also an interferon-stimulated gene p53 5. Hypoxia transcription programming p54 5.1 Biochemical activities and molecular properties of HIF-1α p55 5.2 HIF-1α and cancer p56 5.3 HIF-1α stability p57 5.3.1 The VHL- dependent pathways of HIF-1α regulation p58 5.3.2 VHL-independent pathways of HIF-1α regulation p58 5.4 Factors modulate HIF-1α expression p58 Chapter Two: Materials and Methods p60 Chapter Three: A negative feedback of HIF-1α pathway via interferon-stimulated gene 15 (ISG15) and its conjugating ISGylation pathway p72 Results p73 Interferon (IFN) treatment affects the levels of free HIF-1α protein p73 ISG15 reduces HIF-1α expression p74 ISG15 interacts with HIF-1α p75 HIF-1α is an ISGylation substrate p76 Functional interactions of HIF-1α and ISG15 p78 ISG15 and ISGylation negatively regulate HIF-1α-mediated gene expression: underlying mechanism p79 Discussion p81 Biological impacts of ISG15 on HIF-1α-mediated cellular proliferation and tmorigenesis p81 A crosstalk between inflammatory and hypoxic environments p82 Chapter Four: Interferon-α causes HIF-1α accumulation via the PI3K/AKT/mTOR pathways leading to epithelial-to-mesenchymal transition p86 Results p87 Interferon-α treatments caused HIF-1α accumulation in a concentration- and time-dependent manner p87 IFN-α, but not other cytokines, induced specifically HIF-1α expression p88 The involvement of transcription and translation, but not the VHL-mediated proteasome pathway, in the IFN-α-induced expression of functional HIF-1α p88 Potential molecular mechanisms underlie the IFN-α-activated HIF-1α pathway p90 IFN-α activated AKT, mTOR, NF-kB and GSK3β signaling pathways p92 IFN-α mediated EMT progression via HIF-1α p93 Discussion p97 The relation of inflammation and hypoxia with cancer development p97 Molecular and signaling pathways contributing to the IFN-α-induced HIF-1α expression: the involvements of JAK/STAT1, PI3K/AKT and mTOR/GSK3β pathways p99 Figures p103 Fig. 1 Interferon and ISG15 affect expression levels of ubiquitinylation and HIF-1α p104 Fig. 2 Hypoxia modulates the levels of free ISG15 and ISG15 conjugates p105 Fig. 3 The ISG15-induced reduction of HIF-1α expression is independent of transcription and VHL-associated degradation p106 Fig. 4 Overexpression of non-degradable HIF-1αΔODD leads to the down-regulation of free form of ISG15 protein level, but the increase of ISGylated proteins p107 Fig. 5 ISG15 expression leads to the down-regulation of HIF-1α expression p108 Fig. 6 Ectopic expression of ISG15 leads to the down-regulation of HIF-1α expression in a concentration-dependent manner in Caki-1 and 769-P cells p109 Fig. 7 Transcription and proteasome are not associated with the decrease of HIF-1α by ISG15 expression p110 Fig. 8 ISG15 and IFN modulate DFX-induced HIF-1α expression p111 Fig. 9 ISG15 binds physically to HIF-1α p112 Fig. 10 The association of ISG15 and HIF-1α is hypoxia-inducible p113 Fig. 11 Ectopically expressed HA-tagged HIF-1α localizes with GFP-tagged ISG15 p114 Fig. 12 HIF-1α binds to ISG15 through its N-terminus p115 Fig. 13 The ISG15-interacting domain of HIF-1α is located at its N’-terminus p116 Fig. 14 Mapping the ISG15 binding domain in HIF-1α p117 Fig. 15 Full length ISG15 is required for the binding with HIF-1α p118 Fig. 16 Functional expression of ISGylation causes a decrease in free HIF-1α levels p119 Fig. 17 HIF-1α is an ISGylation substrate p120 Fig. 18 Herc5, compared to EFP, is the major E3 ligase of ISGylation for HIF-1α p121 Fig. 19 VHL is not involved in the ISGylation of HIF-1α p122 Fig. 20 HIF-1α is conjugated by ISG15 at multiple sites p123 Fig. 21 HIF-1α is conjugated by ISG15 at multiple sites p124 Fig. 22 Schematic illustration of the potential ISGylated domains of HIF-1α p125 Fig. 23 ISG15 and ISGylation negatively regulate the transcriptional activity of HIF-1α p126 Fig. 24 ISGylated HIF-1α leads to the diminished expression of Vimentin expression p127 Fig. 25 The ISGylation system also reduced HIF-1α-mediated vimentin expression under normoxia in 293T cells p128 Fig. 26 The ISGylation system also reduced HIF-1α-mediated vimentin, glut1, slug and fibronectin expression under normoxia in 293T and 769-P cells p129 Fig. 27 Expression of ISG15 is inversely to that of HIF-1α target genes p130 Fig. 28 IFN treatment decreased DFX-induced vimentin and glut1 protein expression p131 Fig. 29 Ectopic ISG15 expression reduced the HIF-1α and HIF-1β dimerization p132 Fig. 30 The levels of ubiquitylated HIF-1α proteins were increased with under expression of ISG15 or VHL p133 Fig. 31 ISG15 and ISGylation affected the stability of HIF-1α p134 Fig. 32 ISGylation contributed to the reduction of free HIF-1α levels by ISG15 p135 Fig. 33 Proteasome inhibition blocked ISGylation-associated HIF-1α degradation p136 Fig. 34 ISGylation-mediated reduction of the levels of free HIF-1α was largely independent of HIF-1α hydroxylation p137 Fig. 35 ISG15 expression compromises both cellular proliferation and tumorigenic growth in mice p138 Fig. 36 Ectopic ISG15 expression in 769-P and Caki-1 cells resulted in a much lower anchorage-independent growth of 769-P cells and tumor growth in a mouse xenograft model p139 Fig. 37 The levels of ISG15 and ISGylates in tumor samples extracted from mice p140 Fig. 38 Co-expression of ISG15 greatly reduced HIF-1α-promoted tumorigenic growth in soft agar p141 Fig. 39 Cellular exposure to interferon-α causes an accumulation of HIF-1α proteins p142 Fig. 40 Cellular exposure to interferon-γor LPS has no impact on the expression of HIF-1α p143 Fig. 41 Cellular exposure to interferon-α, leads to up-regulation of downstream genes and protein expression of HIF-1α p144 Fig. 42 IFN-α treatment activates HIF-1α transcriptional activity p145 Fig. 43 IFN-α-induced HIF-1α expression is not associated with E3 ligase (VHL) p146 Fig. 44 Protein synthesis is involved in the modulation of HIF-1α by IFN-α expression, was not associated with protein degradation p147 Fig. 45 Potential molecular mechanisms underlie IFN-α-activated HIF-1α pathway p148 Fig. 46 The PI3K/AKT signaling pathways are involved in the IFN-α-induced expression of HIF-1α p149 Fig. 47 The PI3K/AKT axis is involved in IFN-α-mediated expression of HIF-1α p150 Fig. 48 The mTOR-AKT axis is involved in the IFN-α-mediated expression of HIF-1α p151 Fig. 49 Potential molecular mechanisms underlie IFN-α-activated HIF-1α pathway p152 Fig. 50 IFN-α exposure leads to extensive activation of mTOR, AKT, NF-κb and GSK3β pathways p153 Fig. 51 Activation of GSK3β pathway also participates in the modulation of HIF-1α by IFN-α p154 Fig. 52 IFN-α evoked epithelial-mesenchymal transition through HIF-1α p155 Fig. 53 IFN-α-evoked HIF-1α expression leads to epithelial-mesenchymal transition p156 Fig. 54 IFN-α exposure to 769-P cells resulted in the elevated colony survival and the decreased PARP-1 cleavage p157 Fig. 55 IFN-α treatment promotes invasion ability in 769-P cells through HIF-1α p158 References p159 Curriculum vitae p170 | |
dc.language.iso | en | |
dc.title | 探討發炎與缺氧微環境之交互作用與其對腫瘤發生之影響 | zh_TW |
dc.title | Studies on the potential crosstalk between inflammatory and hypoxic microenvironment linking to cancer development | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 詹迺立,李明學,顧記華,謝小燕 | |
dc.subject.keyword | 發炎,缺氧,干擾素,干擾素刺激基因15,缺氧誘導因子, | zh_TW |
dc.subject.keyword | Inflammation,hypoxia,interferon,ISG15,HIF-1α, | en |
dc.relation.page | 171 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-02-13 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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