請用此 Handle URI 來引用此文件: http://hdl.handle.net/11455/23133
標題: 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
Investigating the Roles of YWHAZ and HLJ1 in Modulating Epithelial-Mesenchymal Transition and Lung Cancer Progression
作者: 陳靜嫻
Chen, Ching-Hsien
關鍵字: YWHAZ
YWHAZ蛋白
HLJ1
Epithelial-Mesenchymal Transition
Lung cancer
HLJ1蛋白
上皮-間葉細胞轉變
肺癌
出版社: 生命科學系所
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摘要: 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。
Metastasis 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.
URI: http://hdl.handle.net/11455/23133
其他識別: U0005-2501201122270300
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2501201122270300
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