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研究生:陳建有
研究生(外文):Chien-Yu Chen
論文名稱:探討第八型岩藻醣轉移酶在人類非小細胞肺癌中過度表現之功能與調控機制
論文名稱(外文):The Functional Role and Regulatory Mechanism of FUT8 Overexpression in Human Non-Small Cell Lung Cancer
指導教授:翁啟惠翁啟惠引用關係
指導教授(外文):Chi-Huey Wong
口試委員:楊泮池余忠仁蕭宏昇林俊宏吳宗益
口試委員(外文):Pan-Chyr YangChong-Jen YuMichael HsiaoChun-Hung LinChung-Yi Wu
口試日期:2013-06-28
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生化科學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:115
中文關鍵詞:岩藻醣核心岩藻醣化α16-岩藻醣轉移酶上皮細胞鈣黏蛋白轉化生長因子-β
外文關鍵詞:FucoseCore fucosylationα16-fucosyltransferaseE-cadherinTGF-β
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第八型岩藻醣轉移酶(fucosyltransferase 8, FUT8)是哺乳類動物中唯一一種可將岩藻醣以α1,6的鍵結方式連接到醣蛋白上的醣化酵素。在過去的研究中,FUT8過度表現的現象曾在多種癌症中被發現,其中包括肝癌、卵巢癌、甲狀腺癌以及大腸直腸癌,且其表現量與這些腫瘤的惡性程度具有正相關性。而在我們先前的研究中,為了解岩藻醣轉移酶與肺癌細胞轉移的相關性,也曾利用即時定量聚合酶連鎖反應(quantitative real time PCR, Q-PCR)比較兩株源自同細胞、但具有不同轉移能力的肺癌細胞株CL1-0與CL1-5之中各種岩藻醣轉移酶的表現量,結果發現與CL1-0相比,FUT8在具有高轉移能力的肺癌細胞株CL1-5中亦有大量表現的現象。然而,雖然已知FUT8的表現量在臨床上與腫瘤的惡性程度有正相關性,但對於FUT8在腫瘤發展的過程中所扮演的角色,至今仍然十分地不清楚。在本研究中,我們首先利用臨床檢體證實FUT8在人類非小細胞肺癌中具有過度表現的現象,且表現量越高的病人,其腫瘤轉移與復發的機率越高,存活率也顯著降低。接著藉由核酸干擾技術(shRNA),我們發現在降低FUT8的表現量後,不論是在試管中(in vitro)或是小鼠體內(in vivo),肺癌細胞的生長、轉移都被顯著地抑制。而我們也透過醣蛋白質體學與核酸微陣列分析技術,分別找到受FUT8所修飾的醣蛋白,以及受其活性所影響的下游基因。結果顯示,FUT8可廣泛地修飾細胞表面的表面抗原(surface antigens)、受體(receptors)以及黏附分子(adhesion molecules),並藉此影響許多與腫瘤發展相關的基因的表現。此外,在這個研究裡我們也找到FUT8在腫瘤發展的過程中過度表現的調控機制:在腫瘤轉移中扮演關鍵角色的一個名為上皮-間葉細胞轉換(epithelial-mesenchymal transition, EMT)的過程中,FUT8的基因表現會受到β-catenin/lymphoid enhancer-binding factor-1 (LEF-1)所活化。而從一個初步的實驗結果我們也發現,FUT8的表現可能與p53的突變與否有關,值得進一步的研究。總結來說,本研究不但提出了一個新的模型來解釋FUT8與肺癌發展之間的因果關係,也提供了一個可能的方向供預後判斷、甚至是治療非小細胞肺癌。

In the past decade, overexpression of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been shown to correlate with malignancy of several human cancers including liver, ovarian, thyroid, and colorectal cancers. We previous also found that FUT8 is dramatically upregulated in a highly aggressive lung cancer cell line CL1-5 comparing to its non-aggressive parental cell line CL1-0. However, little is known about the pathological role of FUT8 in the progression of tumor. Here, we identify FUT8 as a prognostic factor and a functional regulator of nonsmall cell lung cancer (NSCLC). Overexpression of FUT8 in NSCLC is associated with tumor metastasis, disease recurrence and poor patient survival. Experimental knocking down FUT8 in aggressive lung cancer cell lines significantly suppresses their invasion, migration and growth abilities in vivo and in vitro. In addition, we categorize glycoproteins and genes regulated by FUT8 activity using glycoproteomic and microarray approaches. Results from the comprehensive omics analysis indicate that FUT8 globally modifies surface antigens, receptors, and adhesion molecules as well as controls dozens of genes associated with malignancy, suggesting that FUT8 promotes lung cancer progression through multiple mechanisms. Furthermore, in the current study, we unraveled the regulatory mechanism of FUT8 expression in cancer progression. During epithelial-mesenchymal transition (EMT), one of the critical steps in cancer metastasis, the expression of FUT8 is transactivated by β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). Besides, a preliminary study suggests that p53 may also regulate FUT8 expression via cross-talk with β-catenin signaling pathway. Taken together, our results not only provide a novel model to link FUT8 expression with tumor progression, but also point out a promising direction for the prognosis and therapy of NSCLC.

Chapter 1 Introduction 1
1.1 N-Linked Glycosylation 1
1.2 Alpha1, 6-Fucosylation: The Structure, Mechanism, and Function of FUT8 4
1.3 Alpha1, 6-Fucosylation: The Physiological Role and Clinical Correlation of FUT8 7
1.4 Epithelial-Mesenchymal Transition and Tumor Progression 9
1.5 Signaling Cross-Talk between TGF-β and Others in EMT 10
1.6 Specific Aim 13
Chapter 2 Materials and Methods 15
2.1 Materials 15
2.2 Methods 22
2.2.1 Establishment of Stable Cell Lines 22
2.2.2 Cell Invasion and Migration Assays 23
2.2.3 Cell Proliferation Assay 24
2.2.4 Flow Cytometric Analysis 24
2.2.5 Western Blot Analysis 25
2.2.6 Immunohistochemistry 25
2.2.7 Quantitative Real-Time PCR (Q-PCR) 27
2.2.8 Methylation-Specific PCR 27
2.2.9 Glycoproteomic Analysis of Core Fucosylated Glycoproteins in Lung Cancer Cells 29
2.2.10 Gene Microarray Analysis 30
2.2.11 Gelatin Zymography 31
2.2.12 Reporter Assay 32
2.2.13 Xenograft Models 33
Chapter 3 Results 35
3.1 Expression Profiling of Fucosyltransferases (FUTs) in CL1-0 and CL1-5 using Quantitative RT-PCR 35
3.2 Role of FUT8 in Lung Cancer Progression: In Vitro Functional Analysis 35
3.3 Role of FUT8 in Tumor Growth and Lung Metastasis: In Vivo Analysis 37
3.4 Identification of the Active Promoter Regions for FUT8 Overexpression during Tumor Progression 38
3.5 Role of DNA Methylation in FUT8 Expression 38
3.6 Identifying β-catenin as a Transcriptional Activator of FUT8 during Epithelial-Mesenchymal Transition (EMT) 39
3.7 Cross-talk between p53 and β-catenin Signaling Pathways in Regulating FUT8 Expression 41
3.8 Correlation between FUT8 Expression and Clinicopathological Factors in NSCLC 42
3.9 Correlation between the Expression of FUT8 and E-cadherin in Clinical Specimens 43
3.10 Glycoproteomic Analysis of Core Fucosylated Glycoproteins in Lung Cancer Cells 43
3.11 Identification of Genes Modulated by FUT8/Core Fucosylation 45
3.12 Summary 46
Chapter 4 Discussion 47
Chapter 5 Figures 52
Chapter 6 Tables 82
Chapter 7 Reference 100

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