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系統識別號 U0026-1508201413305000
論文名稱(中文) α-Catulin 在癌幹性和癌轉移中扮演之角色
論文名稱(英文) The Role of α-Catulin in Cancer Stemness and Metastasis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 梁鎮顯
研究生(英文) Chen-Hsien Liang
學號 S58971031
學位類別 博士
語文別 英文
論文頁數 115頁
口試委員 召集委員-陳玉玲
口試委員-吳昭良
口試委員-呂佩融
指導教授-洪澤民
口試委員-陳惠文
口試委員-陳健尉
中文關鍵字 癌細胞轉移  肺癌  癌幹細胞 
英文關鍵字 cancer metastasis  lung cancer  cancer stem cell 
學科別分類
中文摘要 肺癌為世界上最常見的惡性腫瘤,而造成肺癌病患高死亡率的主要原因為癌細胞轉移及癌細胞對於藥物治療產生抗藥性。最近有許多研究指出癌症幹細胞為造成癌細胞轉移及抗藥性產生的原因,癌症幹細胞為腫瘤細胞中一小群細胞,對於腫瘤的生成及發展扮演重要角色。因此,針對癌症幹細胞作為治療能提供癌症病患更有效的治療。α-Catulin 為一致癌蛋白能藉由避免細胞衰老來幫助癌細胞生長。最近的研究也指出 α-catulin 的表現量與上皮-間質轉型成正相關。而有越來越多研究指出癌細胞能藉由上皮-間質轉型過程增加癌症幹細胞數量。在我們 cDNA 微陣列分析中發現過度表現 α-catulin 會增加許多肺癌幹細胞標誌及癌轉移標誌的表現。因此 α-catulin 的表現量可能與癌幹細的形成有關。在此我們發現 α-catulin 能分別與 ILK 及 KLF5 交互作用。ILK 為一種絲胺酸/羥丁胺酸蛋白酵素且參與調控細胞生長、抗細胞凋亡、細胞移行/侵襲及血管新生。我們發現過度表現 α-catulin 能促進癌細胞轉移藉由 NFB-ILK 訊息傳遞路徑來增加整合素 αVβ3 及纖維連接蛋白表現。 KLF5 為 kupple-like 家族轉錄因子之一且被發現和調控幹細胞生長有關。我們發現 α-catulin 增加癌症幹細胞特性是藉由避免 KLF5 經由 E3泛素連接酶 WWP1調控之降解進而活化 Oct4 及 Nanog 表現來達成。減弱 α-catulin 或 KLF5皆能降低此兩蛋白造成之癌症幹細胞特性增加。總結來說,我們的結果顯示出 α-catulin 能藉由調控 ILK 及 KLF5 訊息傳遞路徑而在肺癌細胞轉移及肺癌幹細胞生成扮演重要角色。在肺癌病患中,針對 α-catulin 作為標靶治療或許能提供更有效的治療。
英文摘要 Lung cancer is the most common malignant tumors in the world. The high mortality rate in patients with lung cancer is due to cancer metastasis and therapeutic resistance. Many evidences indicate that cancer metastasis and therapeutic resistance are mediated by cancer stem-like cells (CSCs), a small population of cancer cells, which may require for cancer initiation and development. Targeting CSCs may provide effective therapy for human cancers. α-Catulin is an oncoprotein that helps sustain proliferation by preventing cellular senescence. Recent studies have shown that the expression level of α-catulin is positive correlated with epithelial-mesenchymal transition. Increasing evidence suggests that CSCs can be enriched when cancer cells undergo EMT. We also found that several lung cancer stemness genes were upregulated in α-catulin-overexpressing cells. Therefore, the expression of α-catulin may correlate with CSC formation. Here, we found that α-catulin interacted with ILK and KLF5 separately. ILK is a serine/threonine protein kinase and mediates the signaling functions in cell proliferation, anti-apoptosis, migration/invasion and angiogenesis. We found that overexpression of α-catulin promoted lung cancer metastasis through NFB-ILK dependent pathway and increased expression of integrin αVβ3 and fibronectin. On the other hand, KLF5 is a member of the Kruppel-like transcription factor family and has been shown to play important role in maintenance of stem cell self-renewnal. We found that α-catulin enhanced CSC formation through antagonizes the E3 ubiquitin ligase WWP1 mediated KLF5 degradation and activated KLF5 downstream genes Oct4 and Nanog expression. Attenuation of KLF5 or α-catulin reciprocally decreased CSC proterties induced by the other protein. Taken together, our study shows that α-catulin plays a critical role in lung cancer metastasis and CSC formation by activating ILK and KLF5 signaling axes. Targeting α-catulin may be an effective therapy for lung cancer.
論文目次 Abstract in Chinese I
Abstract II
Acknowledgement IV
Contents VI
Table contents IX
Figure contents X
Abbreviation XIII
Chapter1. Introduction 1
1. Lung cancer 1
2. Cancer metastasis 1
3. Cancer stem cell 2
4. α-Catulin 4
5. ILK 5
6. KLF5 6
Objectives of study 8
Chapter2. Materials and Methods 10
Cell culture 10
Reverse transcription-polymerase chain reaction (RT-PCR) analysis 10
Quantitative RT-PCR 11
Western blot assay 12
Confirmation of interaction by yeast-two hybrid 12
Immunoprecipitation and Western blot assay 13
Migration assay 14
Invasion assay 14
Lentiviral generation and infection 15
Xenograft animal model 16
Sphere formation assay 17
Flow cytometric analysis 17
Cytotoxicity assay 17
Luciferase reporter assay 18
Microarray analysis and pathway analysis 18
Chapter3. Results 20
Part 1: The role of α-catulin in cancer metastasis 20
1.1 α-Catulin enhances lung cancer cell migration and invasion 20
1.2 α-Catulin enhances lung cancer cell metastasis in vivo 21
1.3 α-Catulin enhances lung cancer cell migration and invasion through interacted with ILK 22
1.4 α-Catulin promotes the Akt-NF-κB signaling pathway is ILK dependent 23
1.5 α-Catulin activates integrin-ILK-NF-κB positive feedback loop to promote cell migration and invasion 24
1.6 The CTNNAL1 plus ILK 2-gene signature can predict survival in NSCLC patients 26
Part 2: The role of α-catulin in CSCs formation 26
2.1 α-Catulin enhances CSCs properties in lung cancer cells. 26
2.2 α-Catulin interacts with KLF5 29
2.3 α-Catulin enhances CSCs properties through interaction with KLF5 29
2.4 α-Catulin protects KLF5 from WWP1 mediated degradation 30
2.5 α-Catulin is important in KLF5 mediated cancer stemness properties 31
Chapter4. Discussion 33
Chapter5. Conclusion 42
References 43
Tables 61
Figures 71
Appendix 108
Equipments 114


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