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Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23133
DC FieldValueLanguage
dc.contributor楊泮池zh_TW
dc.contributorPan-Chyr Yangen_US
dc.contributor俞松良zh_TW
dc.contributor洪澤民zh_TW
dc.contributor陳惠文zh_TW
dc.contributorSung-Liang Yuen_US
dc.contributor.advisor陳健尉zh_TW
dc.contributor.advisorJeremy J.W. Chenen_US
dc.contributor.author陳靜嫻zh_TW
dc.contributor.authorChen, Ching-Hsienen_US
dc.contributor.other中興大學zh_TW
dc.date2012zh_TW
dc.date.accessioned2014-06-06T07:19:36Z-
dc.date.available2014-06-06T07:19:36Z-
dc.identifierU0005-2501201122270300zh_TW
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dc.identifier.urihttp://hdl.handle.net/11455/23133-
dc.description.abstract肺癌是近年來具有高發生率和極高死亡率之惡性腫瘤，轉移(metastasis)是癌症進程中導致病患死亡的主因。癌細胞侵襲（invasion）是轉移的起始步驟，非侵襲性的腫瘤細胞經由降低細胞黏附因子，失去細胞極性並使細胞骨架重組而造成上皮-間葉的轉變作用(epithelial-mesenchymal transition，EMT），成為具轉移能力的癌細胞。研究指出透過許多訊息傳遞路徑，包括 EGF、Wnt、Src signaling的活化導致特定的轉錄因子大量表現而引發EMT造成癌轉移。為找尋新的癌轉移相關基因，實驗室先前分別以基因體雜合微陣列 (array-CGH)及基因表現晶片(cDNA microarray)，發現具有調控轉移潛力的YWHAZ基因與新的抑癌基因HLJ1，然而兩者在肺癌轉移的分子機制目前並不清楚。為研究YWHAZ與HLJ1調控EMT的角色與機制，本論文分成三個部份探討。在第一部份主要探討YWHAZ蛋白引發肺癌細胞EMT與invadopodia形成之重要性。結果顯示YWHAZ可抑制β-catenin泛素化(ubiquitination)進而活化其訊息傳遞，並在核內形成YWHAZ/TCF4/β-catenin複合體結合至slug的啟動子上而誘導EMT之產生。此外， YWAHZ的Y178磷酸化之後能與 Src結合，並增加Src活性、MMP2分泌與促進invadopodia形成，說明Y178是YWHAZ蛋白具有致癌特性的重要胺基酸。第二部份針對腫瘤酸性微環境，探討HLJ1的酪胺酸磷酸化與骨架蛋白的交互作用。我們發現HLJ1為酪胺酸磷酸化蛋白，Y172的磷酸化會影響HLJ1在細胞內的分布，也說明了酸性逆境下經由增加HLJ1的磷酸化活性與肌動蛋白結合進而抑制癌細胞的移動能力。第三部份為研究HLJ1與Src之交互作用，並鑑定兩者結合的區域，以瞭解HLJ1調控EMT的機制。結果證明HLJ1透過抑制EMT的發生進而控制肺癌之轉移，接著我們發現HLJ1能結合至Src SH3及kinase區域 (domain)，並且抑制Src的活化與其磷酸化下游的能力。更重要的是，我們發現HLJ1能干擾Src下游分子與訊息傳遞路徑包括FAK與β-catenin。另一方面，我們證實HLJ1在Y172的胺基酸位置可被Src誘導磷酸化，並對 HLJ1的抑癌活性相當重要。不僅如此，我們也確認HLJ1 的P301/P304是Src SH3結合區域 (binding motif)，也是HLJ1蛋白具有抑癌特性的重要胺基酸。藉由以上的研究結果，期望可提供調控癌細胞EMT的分子機制，並希望對於癌症臨床治療有所貢獻。zh_TW
dc.description.abstractMetastasis is the major cause leading to mortality for lung cancer patients. In carcinomas, metastasis is a multiple-step process, the first of which is invasion. Cancer cells acquire their invasive capacity by undergoing phenotypic conversion referred to as epithelial–mesenchymal transition (EMT), which is mediated by various pathway including EGF、Wnt、Src signaling and contributes to metastasis. To obtain the novel metastasis-related genes, we used the microarray-based comparative genomic hybridization and affymetrix gene expression profiles to identify the potential candidates, YWHAZ and HLJ1, respectively. To investigate the roles of YWHAZ and HLJ1 in modulating epithelial-mesenchymal transition and cancer progression, three specific parts are included in this dissertation. In the first part, we investigated the importance of YWHAZ in inducing EMT and invadopodia formation. Our results demonstrated that oncogenic functions of YWHAZ are mediated, at least partly, by prevention of ubiquitination ofβ-catenin. Subsequently, the accumulated β-catenin activates β-catenin/TCF signalling and slug-mediated EMT pathway. On the other hand, YWHAZ associates with Src by its phosphorylation at Y178 and positive regulation of Src-induced podosome rings, causing MMP2 secretion and gelatin degradation. In the second part, we focused on the molecular mechanism of HLJ1 on suppressing migration of lung cancer cells in acidic microenvironment. We not only provide evidence that HLJ1 is a tyrosine phosphoprotein but also illustrate HLJ1 binding to actin cytoskeleton during acidic stress and tyrosine phosphorylation-dependent association with β-actin. Finally, the third part of this dissertation presents a new molecular mechanism in HLJ1-Src complex and illustrates an important role for HLJ1 to inhibit EMT. Our findings revealed that HLJ1 associates with Src and represses its activation as well as downstream signaling, including FAK and β-catenin. Meanwhile, we reveal the critical amino acids in HLJ1 for HLJ1-Src interaction and suppressor characteristic of HLJ1. Taken together, these efforts will enhance our understanding on the impact of YWHAZ and HLJ1 on modulation of EMT and may have important implications for future cancer enhancer and suppressor investigations.zh_TW
dc.description.tableofcontents誌謝 i 中文摘要 ii Abstract iii Table of Contents iv List of Figures vii List of Tables ix Abbreviation 1 Preface 3 Chapter I YWHAZ Synergistically Induces Epithelial–Mesenchymal Transition and Invadopodia Formation to Promote Cancer Progression 5 Abstract 6 Introduction 7 Methods 9 Results 19 YWHAZ associated with survival of lung cancer patients 19 YWHAZ is a potential oncogene in lung cancer 20 YWHAZ promotes tumorigenesis and metastasis in vivo 20 YWHAZ induces a neuron-like morphological change and EMT 21 YWHAZ activates slug expression through β-catenin/TCF signalling 22 YWHAZ associates with β-catenin to retard degradation of β-catenin via the ubiquitin-proteasome pathway 23 YWHAZ-β-catenin interaction promotes cancer invasion 24 YWHAZ mediates invadopodia formation and binds to Src by its Y178 phosphorylation 25 Y178 in YWHAZ is a pivotal site for YWHAZ-mediated invadopodia formation and oncogenic functions 26 Discussion 28 Figures 32 Tables 59 Chapter II Acidic stress facilitates tyrosine phosphorylation of HLJ1 to associate with actin cytoskeleton in lung cancer cells 65 Abstract 66 Introduction 67 Methods 69 Results 74 Acidic stress decreased cell migration and up-regulated HLJ1 protein in lung cancer cells 74 Increased tyrosine phosphorylation of HLJ1 by acidic pHe 75 Identification of the sub-cellular distribution of phospho-HLJ1 and its tyrosine-phosphorylated sites 76 Tyrosine phosphorylation of HLJ1 is critical to the interaction with actin cytoskeleton 77 Discussion 79 Figures 83 Chapter III HLJ1 Controls Epithelial-Mesenchymal Transition by Its Binding to Src and Suppressing Src Activation 94 Abstract 95 Introduction 96 Methods 98 Results 105 HLJ1 serves as a suppresser of epithelial-mesenchymal transition (EMT) 105 HLJ1 is a novel interacting protein with Src 105 HLJ1 expression controls Src membrane-targeting and Src activity 106 Src-FAK interaction and tyrosine phosphorylation of FAK were regulated by HLJ1 expression 107 Silence of HLJ1 expression promotes Src binding to β-catenin and nuclear accumulation of β-catenin 108 Full-length HLJ1 directly associates with kinase and SH3 domain of Src 109 Y172 phosphorylation of HLJ1 is crucial for HLJ1 in repressing Src-medicated invasion 110 P301/P304 motif in HLJ1 is essential for HLJ1-Src interaction and suppressor characteristic of HLJ1 111 Analysis of Src activity and HLJ1 expression in mammalian tissues 112 Discussion 114 Figures 119 Conclusion 140 References 141 Plasmid Map 156 Appendix 163 Figure I-1 Analysis of YWHAZ expression in lung cancer cell lines 32 Figure I-2 High YWHAZ expression is correlated with tumorigenesis and poor survival in lung cancer patients 34 Figure I-3 YWHAZ is a potential oncogene in lung cancer 36 Figure I-4 YWHAZ promotes tumorigenesis and metastasis in vivo 38 Figure I-5 YWHAZ induces a neuron-like morphological change and EMT 40 Figure I-6 YWHAZ activates slug expression through β-catenin/TCF signalling in lung cancer cells 43 Figure I-7 The complex of YWHAZ/β-catenin/TCF4 on slug promoter 45 Figure I-8 YWHAZ retards the degradation of β-catenin via the ubiquitin-proteasome pathway 48 Figure I-9 Disruption of YWHAZ and β-catenin complex reduces lung cancer invasion 50 Figure I-10 YWHAZ expression enhances gelatin degradation and formation of F-actin rings 52 Figure I-11 Y178 in YWHAZ is crucial for its binding to Src 54 Figure I-12 Y178 plays an important role for YWHAZ to promote invadopodia formation 55 Figure I-13 Y178 is required for YWHAZ to acquire oncogenic functions 56 Figure I-14 A hypothetical model for the role of YWHAZ in facilitating cancer progression 58 Figure II-1 Effects of acidic stress on lung cancer cell viability, migration, and morphology 83 Figure II-2 Up-regulation of HLJ1 protein by acidic stress 85 Figure II-3 Acidification-induced increase of tyrosine–phosphorylated HLJ1 86 Figure II-4 Identification of the sub-cellular distribution of phospho-HLJ1 and its tyrosine-phosphorylated sites 88 Figure II-5 The sub-cellular distribution of wild-type and mutant V5-HLJ1 protein in normal condition 90 Figure II-6 Acidic stress augments HLJ1 binding to actin cytoskeleton 91 Figure II-7 Tyrosine phosphorylation-dependent association of HLJ1 with β-actin 93 Figure III-1 HLJ1 expression suppresses lung cancer metastasis 119 Figure III-2 HLJ1 inhibits epithelial–mesenchymal transition (EMT) 120 Figure III-3 HLJ1 associates with Src in vivo and in vitro 121 Figure III-4 HLJ1 alters the cellular localization and activity of c-Src 123 Figure III-5 HLJ1 expression suppresses the membrane recruitment and activity of oncogenic Src 124 Figure III-6 Down-regulated tyrosine phosphorylation and Src-FAK interaction upon HLJ1 expression 126 Figure III-7 HLJ1 reduces tyrosine phosphorylation and nuclear accumulation of β-catenin 127 Figure III-8 Full-length HLJ1 directly associates with SH3 and kinase domain of Src 129 Figure III-9 Y172 of HLJ1 is a major phosphorylation site induced by Src 131 Figure III-10 Y172 of HLJ1 is crucial for HLJ1-Src interaction and invasionsuppression of HLJ1 133 Figure III-11 P301/P304 of HLJ1 is the binding site of Src-SH3 domain 134 Figure III-12 P301/P304 of HLJ1 is essential for HLJ1 to inhibit Src activity, tyrosine-phosphorylation levels and EMT 136 Figure III-13 Analysis of Src activity and HLJ1 expression in mammalian tissues 138 Figure III-14 A hypothetical model for the role of HLJ1 in suppressing cancer progression 139 Table 1 P values for log-rank test of each expression leve 59 Table 2 Summary of clinicopathologic features according to YWHAZ expression 60 Table 3 Summary of pathological incidence of lungs in mice by intravenous injection with YWHAZ-expressing cells or mock control 61 Table 4 Comparison of the incidence of tumorigenesis or metastasis between mock and YWHAZ transfectant in SCID mice by orthotopic lung implantation model 62 Table 5 Clinicopathologic characteristics of the NSCLC patients by YWHAZ expression 63 Table 6 EMT-related pathways involved in CL1-0 cells following YWHAZ gene introduction 64zh_TW
dc.language.isoen_USzh_TW
dc.publisher生命科學系所zh_TW
dc.relation.urihttp://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2501201122270300en_US
dc.subjectYWHAZen_US
dc.subjectYWHAZ蛋白zh_TW
dc.subjectHLJ1en_US
dc.subjectEpithelial-Mesenchymal Transitionen_US
dc.subjectLung canceren_US
dc.subjectHLJ1蛋白zh_TW
dc.subject上皮-間葉細胞轉變zh_TW
dc.subject肺癌zh_TW
dc.title探討YWHAZ與HLJ1蛋白在調控上皮-間葉細胞轉變與肺癌進程之角色zh_TW
dc.titleInvestigating the Roles of YWHAZ and HLJ1 in Modulating Epithelial-Mesenchymal Transition and Lung Cancer Progressionen_US
dc.typeThesis and Dissertationzh_TW
item.openairetypeThesis and Dissertation-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en_US-
item.grantfulltextnone-
item.fulltextno fulltext-
item.cerifentitytypePublications-
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