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系統識別號 U0026-0807201712525200
論文名稱(中文) 食道鱗狀細胞癌SLIT2轉移相關性機制與經營養改善方案之探討
論文名稱(英文) Investigation for SLIT2 Metastasis-related Molecular Alteration in Esophageal Squamous Cell Carcinoma and Potential Management through Nutritional Improvement
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 105
學期 2
出版年 106
研究生(中文) 張家銘
研究生(英文) Chia-Ming Chang
學號 S98971089
學位類別 博士
語文別 中文
論文頁數 79頁
口試委員 指導教授-賴吾為
指導教授-王憶卿
口試委員-曾堯麟
口試委員-方信元
召集委員-蘇五洲
口試委員-劉校生
口試委員-許瀚水
中文關鍵字 SLIT2  Cdc42  Focal adhesion kinase  食道鱗狀細胞癌  營養  細內視鏡經皮穿刺胃造廔 
英文關鍵字 SLIT2  Cdc42  Focal adhesion kinase  esophageal squamous cell carcinoma  nutrition  PEG 
學科別分類
中文摘要 食道鱗狀上皮細胞癌 (esophageal squamous cell carcinoma ; ESCC) 佔台灣食道癌大部分,好發生於重度飲酒患者。吞嚥困難症狀常導致病患營養不良、惡病質,更易使後續治療提早中斷。此外,食道癌容易沿淋巴蔓延導致遠處轉移,即使在現今多方治療策略下癒後仍然不佳。因此,我們研究目標希望探討食道鱗狀上皮細胞癌轉移基因相關機制,不單只是希望作為預後指標,更可能作為提供潛在性治療標的。癌轉移是多步驟過程,其包括腫瘤細胞侵犯淋巴和血管,更進一步轉移至遠端器官。因此,對於轉移相關基因調控途徑的了解將是發展ESCC有效治療方式和診斷方法有著迫切需要。
SLIT2屬於分泌型蛋白,過去已被發現可使Cdc42 GTPase失去活性進而影響神經細胞的遷移有負向導引作用,且在數個人類癌症上有研究證實其具有癌症抑制基因的作用。然而,細胞遷移機轉上SLIT2調控Cdc42的角色在ESCC尚未確立。我們在本研究中利用ESCC臨床檢體、細胞膜式,與動物模式分析,結果證實SLIT2可抑制細胞爬行與轉移的能力,由臨床數據分析也證實可作為疾病預後的生物指標。首先,透過DNA甲基化分析顯示SLIT2啟動子共有28% (14/50)高度甲基化,導致有SLIT2 mRNA有36% (18/50)低表達與31.8% (49/154) 的腫瘤 SLIT2蛋白低表達。此外,SLIT2蛋白低表達與疾病總體存活率與帶病存活率較差有顯著相關 (p < 0.001, p 0.004)。第二,在細胞研究中證實抑制SLIT2表現可以促進癌細胞爬行能力;反之,過度表達SLIT2可以降低細胞爬行能力;此外,用來自過度表達SLIT2的細胞的條件培養基處理的ESCC細胞其遷移能力也會被抑制。重要的是,SLIT2低表達減少srGAP1/Cdc42複合物的形成,從而誘導Cdc42活性並促進focal adhesion kinase及Paxillin在細胞膜上表達。第三,在動物模式癌轉移模型中利用抑制SLIT2表現的ESCC細胞株證實SLIT2具有抑制癌轉移現象。最後,由於DNA甲基化有研究顯示會受到營養因子影響,我們在臨床上於ESCC病患治療前,運用超細內視鏡經皮穿刺胃造廔手術(PEG)嘗試治療病患營養不良狀況,初步結果顯示PEG在我們食道癌病患有極高的成功率,此外也觀察到病患營養狀況停止持續惡化。
結語,研究結果顯示我們提供了新的證據證明SLIT2的低表達與ESCC疾病不良預後相關,並透過Cdc42調控路徑進而促進ESCC的轉移。
英文摘要 Esophageal squamous cell carcinoma (ESCC) comprised the majority of esophageal cancer in Taiwan and tends to occur in patients with heavy alcohol consumption. Symptomatic dysphagia caused common patient malnutrition, cachexia and premature treatment termination. In addition, early lymphatic spread and following distant metastasis lead to poor prognosis, even under current multi-modality treatment protocol. Therefore, we aimed to investigate metastasis-related gene alteration in ESCC, not only to be a prognostic indicator but as a potential treatment target.
SLIT2, a secreted glycoprotein, has been found to inactivate Cdc42 GTPase for repulsive axonal guidance, and silenced in some human cancers as a tumor suppressor gene. However, alteration of SLIT2-mediated Cdc42 in terms of migration regulation remains unclear in ESCC. We reported here in ESCC clinical tumor sample, cell and animal models that SLIT2 acts as a migration and metastasis suppressor. Firstly, in clinical ESCC sample, DNA methylation analysis showed an overall 28% (14/50) SLIT2 promoter hypermethylation, responsible for 36% (18/50) low SLIT2 mRNA expression, and 31.8% (49/154) low SLIT2 protein expression, shown in immunohistochemistry study. Further, low SLIT2 protein expression correlated well with poor overall survival and disease-free survival in ESCC patients (p<0.001, p = 0.004). Secondly, in cell model, knockdown of SLIT2 increased ESCC cell migration, while SLIT2 overexpression reduced cell migration. Further, ESCC cells treated with conditioned media from cells overexpressing SLIT2 also suppressed cell migration. Importantly, silencing of SLIT2 decreased the complex formation between srGAP1 and Cdc42, thus induced Cdc42 activity and promoted membrane localization of focal adhesion kinase and Paxillin. Thirdly, anti-metastatic effect of SLIT2 was confirmed in animal metastasis model with SLIT2 knockdown ESCC cells via tail vein injection. Lastly, because nutritional factors had been proposed to affect DNA methylation, we tried to utilize the ultrathin percutaneous endoscopic gastrostomy (PEG) to improve common malnutrition patient status in locally-advanced ESCC patients. Good PEG successful rate and ceased patient nutritional deterioration were observed in our preliminary data.
In conclusion, our results provide novel evidence that low SLIT2 expression correlates with poor prognosis and promotes migration and metastasis in ESCC, which may be regulated via the Cdc42-mediated pathways.
論文目次 Chapter 1 Introduction 1
1.1 Overview of SLIT2 Signaling Pathway 2
1.2 SLIT2 in Nervous System 3
1.3 The Alteration of SLIT2 and as a Tumor Suppressor Gene in Human Cancers 4
1.4 Diet influence on DNA Hypermethylation and Nutritional Improvement in ESCC 5
1.5 Thesis Aims 6
1.6 Figures and Tables 8
Chapter 2 Low SLIT2 Protein Expression Correlates with Poor Prognosis in ESCC Patients 10
2.1 Background and Aims 10
2.2 Materials and Methods 11
2.3 Results 14
2.3.1 SLIT2 Protein Expression and Its Clinical Correlation 14
2.3.2 Correlation between DNA Methylation, mRNA, and Protein Expression of SLIT2 in ESCC Patients 15
2.4 Discussion 16
2.5 Figures and Tables 17
Chapter 3 SLIT2 Suppresses ESCC Tumor Migration and Metastasis in Vitro 26
3.1 Background and Aims 26
3.2 Material and Methods 27
3.3 Results 31
3.3.1 SLIT2 Is Reactivated by 5-aza-dC Treatment 31
3.3.2 Knockdown or Ectopically Expressed SLIT2 Influences the Migration of ESCC Cells 31
3.3.3 ROBO1 Is Relatively Low-expressed in ESCC But Not Associated with Prognosis. 33
3.3.4 SrGAP1-Cdc42 Signaling Is Involved in SLIT2-Mediated Migration Suppression in ESCC 34
3.3.5 Translocation of p-FAK and p-Paxillin Is Involved in SLIT2-Mediated Migration Suppression 35
3.4 Discussion 35
3.5 Figures and Tables 37
Chapter 4 Loss of SLIT2 Accelerates ESCC Lung Metastasis in Animal Model 49
4.1 Background and Aims 49
4.2 Material and Method 49
4.3 Results 50
4.3.1 SLIT2 Expression Negatively Correlates with Tumor Metastasis in Vivo 50
4.3.2 SLIT2 Expression Negatively Correlates with Membrane Expression of p-FAK and p-Paxillin in Vivo 50
4.4 Discussion 51
4.5 Figures and Tables 52
Chapter 5 Potential Management through Nutritional Improvement using Ultrathin PEG in ESCC patients 54
5.1 Background and Aims 54
5.2 Material and Method 55
5.3 Results 57
5.4 Discussion 58
5.5 Figures and Tables 60
Chapter 6 General Discussion. Conclusions and Prospects 63
6.1 Experimental Findings and Conclusions 63
6.2 Proposed SLIT2 Alteration Pathway and Prospects 68
Bibliography 71
Publication Lists 77
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