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系統識別號 U0026-2008201500140600
論文名稱(中文) Disabled-2基因與TGF-β的訊息傳遞路徑在食道鱗狀細胞癌的角色
論文名稱(英文) The roles of Disabled-2 and TGF-β signaling pathway in esophageal squamous cell carcinomas
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 103
學期 2
出版年 104
研究生(中文) 王文倫
研究生(英文) Wen-Lun Wang
學號 S98981107
學位類別 博士
語文別 英文
論文頁數 71頁
口試委員 指導教授-許博翔
指導教授-呂政展
召集委員-吳明賢
口試委員-楊曉白
口試委員-楊燿榮
口試委員-張維倫
中文關鍵字 Disable-2蛋白  調節性T細胞  食道癌  存活率  區域致癌現象  併發性腫瘤  細胞免疫 
英文關鍵字 Disabled-2  Regulatory T cells  Esophageal squamous cell carcinomas  Survival  Field cancerization  synchronous neoplasm  Cellular immunity 
學科別分類
中文摘要 背景:食道癌是世界上常見的癌症之一,近年來已然成為臺灣之新興癌症且發生率仍在快速增加當中。即使近年來治療上的進展,食道癌患者的存活率仍然非常的差,五年存活率不到20%,主要原因就是患者即使在完整的治療之後,仍有相當高的腫瘤復發率,且經常合併頭頸部癌症一起產生區域致癌現象(Field cancerization)。Disable-2 (DAB2)是一個重要的腫瘤抑制因子,可以抑制許多和癌症相關的訊息傳遞路徑(包括TGF-β、ERK等);近年來許多研究也顯示,TGF-β誘導之調節性T細胞(Regulatory T cell)可以讓腫瘤逃脫宿主的免疫監測機制,使得腫瘤進一步進展、惡化;本研究藉由臨床以及基礎的研究,探討DAB2及調節性T細胞在食道癌以及食道之區域致癌現象所扮演的角色。
方法: 本研究共收集200位患者的腫瘤檢體 (包括100位單獨罹患食道癌,50位單獨罹患頭頸部癌症,以及50位同時具有食道癌及頭頸部癌患者),利用免疫組織化學染色法,分析DAB2蛋白的表現量,以及腫瘤中調節性T細胞的數目,其結果也和腫瘤的臨床特徵如腫瘤分期、存活率以及復發率作比對分析;此外,利用基礎實驗,分別以西方點墨法(western blot)和傷口癒合試驗 (wound healing test)等分析食道癌細胞株當中DAB2, ERK, β-catenin, E-cadherin and N-cadherin等蛋白的表現量及相對應之癌細胞的移動能力;並以基因失去作用(siRNA knockdown)及過度表現(overexpression)的實驗進一步驗證,是否DAB2的表現量會影響食道癌細胞的侵犯能力以及TGF-β所媒介之上皮細胞間質轉化(epithelial-mesenchymal transition, EMT)的產生;調節性T細胞的數目及密度,也和其相關的免疫抑制細胞激素 (IL 10, IL-35 and TGF β)作比對分析;為了探討DAB2基因上游的調控機轉,則利用Methylation-specific PCR檢測DAB2基因啟動子的甲基化狀態。
結果:在一百位食道癌患者的腫瘤檢體中,有四十五位是屬於低DAB2表現的腫瘤,這些腫瘤的體積多較大,且有較深層的腫瘤侵犯、及較高的淋巴結轉移比率;而罹患低DAB2表現腫瘤的患者,具有顯著較差的存活率及較高的腫瘤復發率;COX迴歸分析也確認DAB2表現量可作為預測患者存活率及復發率的指標。藉由體外食道癌細胞株的研究,發現DAB2表現量較低的腫瘤,具有較強的細胞移動能力,不論是利用siRNA來抑制DAB2基因的表現,或利用基因再表現的方法,均證實DAB2的表現量會影響食道癌細胞的侵犯能力,可能的機轉是透過ERK訊息傳遞路徑的活化。至於DAB2基因上游的調控機轉,其啟動子的過度甲基化,只出現在一小部分低DAB2表現腫瘤(13/45; 29%);關於DAB2在TGF-β媒介之上皮細胞間質轉化(EMT)方面,可見上皮細胞間質轉化(EMT)只出現在高DAB2表現的腫瘤,而其表現與否也只會影響具有高DAB2表現腫瘤患者的存活率及復發率。至於在調節性T細胞的研究方面,腫瘤中調節性T細胞的數目和DAB2表現量並沒有顯著的相關性,且反而常出現於較早期的食道癌當中;在同時具有食道癌及頭頸部癌的患者,其調節性T細胞的數目比起單獨罹患食道癌或單獨罹患頭頸癌者顯著較高,是以定量分析腫瘤中調節性T細胞的數目,可作為預測患者罹患多發性癌症的有效指標;腫瘤中調節性T細胞的數目也和患者血清中細胞激素IL 10濃度呈現正相關,在同時罹患食道癌及頭頸部癌者,其血清中細胞激素IL 10、 IL-35、TGF β的濃度都明顯較高,若血清中同時具有三種高濃度的細胞激素,有7.8倍罹患多發性癌症的風險;我們也發現併發多發性癌症的患者,罹患結核菌感染的比率比起單獨食道癌或單獨頭頸癌者高(20% vs. 4%),這也提供併發多發性癌症的患者免疫低下的佐證。
結論: DAB2表現量可以作為預測食道癌患者存活率及復發率的指標,對於具有低DAB2表現腫瘤患者,應採取更緊密的監測及更積極性的治療。藉由對於DAB2基因及TGF-β訊息傳遞路徑在上皮細胞間質轉化(EMT)角色的探討,提供了新的藥物標的,將來可用於改善患者預後。本研究也發現免疫缺陷可能容易導致多發性腫瘤的發生,而定量分析腫瘤中調節性T細胞的數目,可以作為臨床上預測患者罹患多發性癌症的指標,有助於進一步擬定腫瘤篩檢及追蹤的策略。
英文摘要 Background: Patients with esophageal squamous cell carcinomas (ESCCs) have poor survival and frequently developed with synchronous head and neck squamous cell carcinomas (HNSCCs) . Disabled-2 (DAB2) is a crucial tumor suppressor for multiple signaling pathways (ERK, TGF-β etc.) and emerging evidences suggest TGF-β-induced regulatory T cells (Treg) enable tumor cells to escape immunosurveillance, resulting in tumor progression. We aimed to investigate the significance of DAB2 expression and Treg infiltration in ESCC and the field cancerization of esophagus at clinical and cellular levels.
Methods: Tumor tissues of 200 patients (100 ESCC only, 50 HNSCC only, and 50 synchronous SCCs) were evaluated for DAB2 expression and quantitatively accessed for the tumor infiltrating Treg by immunohistochemistry, and then correlated to the clinical features. Expressions of DAB2, ERK, β-catenin, E-cadherin and N-cadherin in ESCC cell lines and cell migration abilities were evaluated by western blot and wound healing assay, respectively. siRNA knockdown and over-expression studies were performed to validate the association between DAB2 and cell behavior. The density of Treg was also correlated to the level of Treg-associated inhibitory cytokines (IL 10, IL-35 and TGF β), and chemokine (CCL22). To explore the upstream regulatory mechanism of DAB2, the methylation status of DAB2 promoter were analyzed by Methylation-specific PCR.
Results: Forty-five ESCC patients had low-DAB2 expression, and significantly had larger tumor size, deeper invasion depth, lymph node metastasis, worse survival, and higher recurrence rate (P<0.05). The Cox-regression model revealed low-DAB2 expression was an independent factor of poor survival (P<0.05), and also of tumor recurrence with the predictive performance superior to clinical TNM stage (P<0.05). Low-DAB2 cancer cells, validated by DAB2 knockdown or over-expression, had higher phosphorylated ERK and migration abilities. Promoter hypermethylation accounted only for a small subset of low-DAB2 cancers. TGF-β-induced epithelial-mesenchymal transition (EMT) only existed in the high-DAB2 cells, and related to worse prognosis of high-DAB2 ESCC (P<0.05). Tumor infiltrating Treg densities were not associated with DAB2 expression levels (P=0.77), and frequently inversely correlated with the tumor stage. The density of tumor infiltrating Treg in the index tumor (i.e. the first malignancy diagnosed) of synchronous SCC group was higher than those of HNSCC or ESCC only (P<0.05). Selecting the optimal cut-off value of Treg density as 34.6 cells/mm2 by ROC curve, an increased Treg density of the index tumor can be an independent factor for developing synchronous SCCs (OR: 6.13; 95% CI: 2.84-13.26). The Treg density was positively correlated with serum IL-10 level and the degree of CCL22-positive cells infiltration in tumor. Furthermore, the serum inhibitory cytokine levels were higher in synchronous SCC group. Concomitant elevation of serum IL-35, TGF-β and IL-10 level is an independent risk factors of developing synchronous cancers (OR: 7.86, 95% CI: 2.14-28.90). The finding of a higher prevalence of tuberculosis infection in the patients with synchronous phenotype than those with non-synchronous group (20% vs. 4%, p=0.001), also provided an indirect evidence that the cellular immunosuppression in the patients with synchronous multiple cancers.
Conclusions: DAB2 expression could be a biomarker to identify patients with worse survival and high recurrence. Our data suggest a means to stratify patients who require more aggressive surveillance and may benefit clinically from anti-ERK or anti-TGF-β therapies. Also, a more severe defect in cellular immunity may predispose to multifocal tumor. The Treg cell number in SCC may serve as a novel predictive biomarker for the risk of synchronous cancer development to initiate a proper surveillance strategy.
論文目次 摘要..........i
Abstract..........iii
Acknowledgement........v
Table of Contents.........vi
List of Tables.........viii
List of Figures......... ix
Abbreviations........ xi
1.Chapter I: Introduction......1
1.1 Esophageal cancer.......1
1.2 Field cancerization phenomenon over the upper aerodigestive tract........2
1.3 Human disabled homolog 2 and TGF-β signaling pathway..........4
1.4 Dissertation Aims........6
1.5 Figures and Tables.......7
2.Chapter II: The roles of Disabled-2 and TGF-β signaling pathway in esophageal SCCs......8
2.1 Background.........8
2.2 Methods........9
2.2.1 Patients and study design......9
2.2.2 Immunohistochemistry for DAB2, Erk phosphorylation and EMT phenotype.......10
2.2.3 Cell culture, Plasmids and Small Interference RNA Transfection........11
2.2.4 Western blot analysis.......12
2.2.5 Wound closure motility assay and transwell migration assay...........12
2.2.6 Methylation-specific PCR to define the methylation status of DAB2 promoter......13
2.2.7 Statistical analysis......13
2.3 Results..........14
2.3.1 Demographics of the ESCC patients with high- and low-DAB2 expressions........14
2.3.2 DAB2 expression and the survival of patients with ESCC..........14
2.3.3 DAB2 expression Levels and ESCC recurrence...14
2.3.4 Low DAB2 ESCC constitute higher migration abilities..15
2.3.5 Low Disabled-2 promotes tumor progression via activation of ERK signaling......15
2.3.6 The association between DAB2 expression level and TGF-β-induced EMT........16
2.3.7 Association between DAB2 and tumor infiltrating regulatory T cells........16
2.3.8 Methylation status of DAB2 promoter in ESCC...17
2.4 Discussion.........17
2.5 Figures and Tables.......21
3.Chapter III: The roles of Disabled-2 and regulatory T cells in the field cancerization phenomenon over upper aerodigestive tract........ 35
3.1 Background.........35
3.2 Methods........37
3.2.1 Patients and study design......37
3.2.2 Clinicopathologic features and survival follow-up of SCC patients.........37
3.2.3 Quantification of regulatory T cells and CCL22-positive cells by IHC.........38
3.2.4 T cell proliferation and in vitro suppression assay..........38
3.2.5 Serum levels of IL 35, IL 10, TGF β by ELISA...39
3.2.6 Statistical analysis.......39
3.3 Results.........40
3.3.1 Clinical characteristics & survival of the different SCC groups..........40
3.3.2 Significances of DAB2 expression on synchronous cancer development........40
3.3.3 Higher tumor infiltrating regulatory T cells in the synchronous SCC........41
3.3.4 Independent risk predictor as synchronous SCC in UADT..........41
3.3.5 The correlations between Treg density with Treg-associated cytokines....... 42
3.3.6 Treg-associated cytokine level predict the synchronous cancer risk..........42
3.3.7 Higher prevalence of tuberculosis infection in synchronous cancer patients.......43
3.4 Discussion.........43
3.5 Figures and Tables........47
4.Chapter IV: Summary and Perspectives....60
References.........63
Publication list........70
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