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研究生:戴達英
研究生(外文):Dar-In Tai
論文名稱:腫瘤壞死因子訊息傳導途徑及核因子kappaB的活化在慢性肝炎及肝癌病患之意義
論文名稱(外文):The significance of Tumor Necrosis Factor Signal Transduction Pathway and NF-kB Transactivation Activity in Chronic Hepatitis and Hepatocellular Carcinoma
指導教授:張學賢蔡順隆蔡順隆引用關係
指導教授(外文):Kenneth S.S. ChangSun-Lung Tsai
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2000
畢業學年度:89
語文別:中文
中文關鍵詞:腫瘤壞死因子腫瘤壞死因子受體核因子kappaB肝癌B型肝炎病毒C型肝炎病毒
外文關鍵詞:Tumor necrosis factorTumor necrosis factor receptorNuclear factor kappaBHepatocellular carcinomaHepatitis B virusHepatitis C virus
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腫瘤壞死因子 (TNF) 是多功能的細胞激素,它能誘導細胞程式性自殺,激發炎症反應來清除病毒,也能活化核因子kappaB (NF-kB) 以刺激組織再生。 其所造成的炎症反應亦是 B型肝炎與C型肝炎病毒相當重要的致病機制。 NF-kB 的活化可以抑制 TNF-誘導的細胞程式性自殺,阻礙了TNF 及其它細胞激素對抗病毒的作用,可能因而促成病毒的持續感染與肝癌形成。 我們檢查慢性B型與C型肝炎C病人的血清及肝組織,及能表達C型肝炎病毒核蛋白之肝癌細胞株中TNF-NF-kB 的活動狀況,以探討病毒的持續感染,致病及致癌的機制。
38位慢性B型肝炎,40位慢性C型肝炎以及9位慢性B與C型肝炎病患接受門診肝生檢檢查當天血漿,以ELISA來定量可溶性腫瘤壞死因子受體I、II及相關之細胞激素。 TNFR-I 及 TNFR-II 的 mRNA以 RT-PCR方式來測量。分析結果發現腫瘤壞死因子受體I與肝炎症反應有正相關,而第一型助手細胞激素在炎症較激烈的慢性B與C型肝炎組較高。 當各組分別分析,在慢性B肝炎組肝炎症反應與可溶性腫瘤壞死因子受體I有正相關, 而慢性C型肝炎組肝炎症反應則僅與可溶性腫瘤壞死因子受體II有正相關。 因為TNFR-I 及 TNFR-II肝內的 mRNA表達,在慢性B型肝炎及慢性C型肝炎之間並無差異,顯示TNFR-I訊息傳導途徑在慢性C型肝炎有受到調節現象,以至於TNFR-I炎症反應作用受阻,可能與其致病性有關。
C型肝炎病毒核蛋白是一個多功能的蛋白質。 它能與腫瘤壞死因子受體I 的死亡區以及淋巴毒素受體細胞體內部份結合,暗示它可能牽涉到產生或對抗細胞自殺之息訊傳導系統。以蛋白質凝膠電泳移動位置改變試驗以及組織免疫染色法來探測受到C 型肝炎病毒感染的肝組織及能表達C 型肝炎病毒核蛋白之肝癌細胞株中,NF-kB 之活性。 然後以高溫培養、加入于擾素g、以及NF-kB抑制劑,來探討腫瘤壞死因子對能與不能表達C型肝炎病毒核蛋白之培養細胞株對細胞自殺作用之差異。 結果在蛋白質凝膠電泳移動位置改變試驗,以及組織免疫染色法都發現C型肝炎病毒感染的肝組織,及能表達C 型肝炎病毒核蛋白之肝癌細胞株中NF-kB之活性皆有增強之現象。 而且能表達C 型肝炎病毒核蛋白之肝癌細胞株,對腫瘤壞死因子誘導的細胞自殺有拮抗作用。 以PDTC 抑制NF-kB,可使能表達C 型肝炎病毒核蛋白之肝癌細胞株,對腫瘤壞死因子誘導的細胞自殺的拮抗作用消失。 因此C 型肝炎病毒核蛋白對腫瘤壞死因子與NF-kB傳導途徑的調控,可能使腫瘤壞死因子受體I引導的肝炎症反應受阻,因而與C 型肝炎病毒持續感染及致病機制有關。
為瞭解NF-kB 在肝癌組織活動狀況,對65位接受部分肝切除的肝癌患者以及9位正常的肝組織,以組織免疫染色法來探測在細胞核內的活化型RelA及 核內的IkBa 在肝癌與非肝癌組織中的表達的差異。另外粹取24位肝癌患者以及9位正常肝之新鮮肝組織之蛋白質,以核蛋白質凝膠電泳移動位置改變試驗來探測NF-kB與DNA結合的活性,另以西方墨點法來探測RelA及 IkBa 在肝癌與非肝癌組織中的表達。 結果發現組織免疫染色法出現NF-kB核染色之機率,蛋白質凝膠電泳移動位置改變試驗探測NF-kB之活性,以及西方墨點法法來探測RelA之表達,皆為肝癌組織高於非肝癌組織。 細胞質中IkBa 的表達則肝癌組織低於非肝癌組織。 綜合以上之結果,活性之NF-kB複合體之表達在肝炎病毒感染之組織較正常組織為高。 同時肝癌組織亦高於非肝癌組織。 NF-kB過度的表達加上IkBa 自行調控的機制不良,可能是肝癌細胞發展的重要因素。

Tumor necrosis factor (TNF) is a multifunction cytokine that plays important roles in the program cell death, inflammatory response and viral clearance. On the othre hand, TNF may promote cell regeneration by activate Nuclear factor kappB (NF-kB) transactivation pathway. The cytotoxicity induced by TNF plays an important role in the pathogenesis of chronic hepatitis B and C. The activation of NF-kB may inhibit apoptosis that may faccilitate viral persistent and hepatocarcinogenesis. For better understanding the differences of persistent infection and pathogenesis between chronic hepatitis B and C, we studied 38 patients with chronic hepatitis B, 40 with chronic hepatitis C, 9 with dual hepatitis B and C for cytokine levels and compared with 12 healthy controls. Plasma levels of TNFa, soluble TNF receptor-I (TNFR-I), soluble TNF receptor-II (TNFR-II) and related cytokines were quantified by ELISA and correlated with histology activity index. Expressions of TNFR-I and II in liver tissues were also examined in 33 with HBV and 15 with HCV by semi-quantitative reverse transcription- polymerase chain reaction (RT-PCR). The results showed that sTNFR-I levels correlated with liver inflammation in the whole study patients. Type 1 helper T cells (Th1) cytokines levels were higher in the groups with higher inflammatory activities. Most importantly, sTNFR-I levels correlated with liver inflammation in HBV, whereas sTNFR-II levels correlated with liver inflammation in HCV. The expressions of TNFR-I and -II messanger RNA (mRNA) in liver tissues were similar and comparable between hepatitis B virus (HBV) and hepatitis C virus (HCV). These findings suggest that TNFR signal transduction pathway is differentially modulated between HBV and HCV infection, and may be relevant to immunopathogenesis.
The HCV core protein is also a multifunctional protein. It may bind to the death domain of TNFR-I, and to the cytoplasmic tail of lymphotoxin-b receptor, implying that it may be involved in the apoptosis and anti-apoptosis signaling pathways. To address this issue, electrophoretic mobility shift assay and immunohistochemical studies were used to demonstrate the activation of NF-kB in HCV-infected liver tissues and in HCV core-transfected cells. The activation of NF-kB was correlated with the apoptosis assays. The results showed that NF-kB activation could be demonstrated in HCV-infected livers and HCV core-transfected cells. The data of electromobility shift assay (EMSA) correlated with those of immunohistochemical studies which revealed a higher frequency of NF-kB nuclear staining in HCV-infected than in normal livers. NF-kB activation conferred resistance to TNFa-induced apoptosis in HCV core-transfected cells. Inhibition of NF-kB activation by pyrrolidine dithiocarbamate sensitized them to TNFa-induced apoptosis. These findings suggest that HCV infection may cause anti-apoptosis by activation of NF-kB and implicate a mechanism by which HCV may evade the host's immune surveillance leading to viral persistence and possibly to hepatocarcinogenesis.
The NF-kB activation status in hepatocellular carcinoma (HCC) has not yet been explored, therefore. immunohistochemical stainings were done on formalin fixed liver tissues from 65 HCCs and 9 normal control subjects to search for active nuclear RelA and nuclear IkBa proteins. Nuclear extract from 37 pairs of fresh frozen tumor and non-tumor liver tissues and 7 normal controls were tested for NF-kB-DNA binding activity by electrophoretic motility shift assay. The RelA and IkBa protein expressions were studied by Western blotting. Nuclear NF-kB stainings were significantly more abundant in HBV or HCV infected tumor as well as non-tumor part of HCC than in normal controls. Nuclear NF-kB-DNA binding activity and nuclear RelA proteins expression were higher in tumor than in non-tumor tissues; whereas, cytosolic IkBa protein expression was generally higher in non-tumor than in tumor tissues. Constitutive activation of NF-kB was found more frequently in tumor than in non-tumor tissues. NF-kB overexpression accompanied by dysregulation of IkBa may play a role in hepatocarcinogenesis of HBV or HCV infection.

封面
目錄
指導教授推薦書
口試委員審定書
授權書
志謝
中文總摘要
英文總摘要
縮寫目錄
1、綜論
圖1-1 腫瘤壞死因數訊息傳導途徑
圖1-2 NF-Kb訊息傳導系統及自動調階機制簡圖
2、 第一步:慢性B與C型肝炎對腫瘤壞死因數受體I與II的不同調空 Differential Modulation of Tumor Necrosis Factor Receptor I and II in Chronic Hepatitis B and C
2-1 中文摘要
2-2 英文摘要
2-3 引言
2-4 材料及方法
2-4-1 材料
2-4-2 病毒學檢測
2-4-3 組織病理檢查
表 2-1 各類慢性病毒性肝炎組及正常人的基本資
2-4-4 細胞激素測定
2-4-5 肝內TNFR-I及TNFR-II訊息核糖核酸半定量測量
2-4-6 統計分析
2-5 結果
表2-2 細胞激素及腫瘤壞死因數受體血漿濃度在不同的慢性病毒性肝炎及正常人之差異血漿
圖2-1 sTNFR-I值在正常足於不同病毒感染組織差異
圖2-2 在全部受檢者中血漿 sTNFR-I值和肝組織炎症反應指數(HAI-I)相關圖。
圖2-3 HBV組中血漿Stnfr-I值和肝組織炎症反應之書(HAI-I)相關圖
圖2-4 HCV組中血漿Stnfr-II值和肝組織炎症反應之書(HAI-I)相關圖
圖2-5 HBV DNA 及HCV RNA值和肝組織炎症反應之書(HAI-I)相關圖
圖2-6 在HBV與HCV組肝組織中Stnfr-ImRNA值之比較圖
2-6 討論
3 第二步:C型肝炎病毒感染活化核因數kappaB與致病性關連
Activation of NF-kB in Hepaitis C Virus Infection:Implications for Pathogenesis and Hepatocarcinogesis
3-1 中文摘要
3-2 英文摘要
3-3 引言
3-4 材料及方法
3-4-1 細胞培養
3-4-2 肝組織
3-4-3 核與細胞質的蛋白質碎取
表3-1 使用於免疫組織染的肝組織之病人基本資料
3-4-4EMSA study
3-4-5 TNFa-誘導的程式性自殺
表3-2 本研究使用的探針及引子
3-4-6 在HCV感染的肝臟以免疫組織染色檢查活化的NF-Kb
3-4-7 針對HCV感染的肝組織及能表達HCV核蛋白質感癌細胞株檢測Fas,TNFR-I及TRAF3的表達
3-5結果
3-5-1HCV-感染的肝組織及RCEβ-轉植的HepG2細胞株能活化NF-kB
3-5-2RCEβ-轉植的HepG2細胞株抑制TNFα-誘導的細胞程式性自殺
圖3-1.HVC的感染能活化NF-kB
圖3-2.競爭性試驗
3-5-3抑制NF-kB的活化使HCV-轉植的細胞株對TNFα-誘導的細胞程式性自殺產生
圖3-3.超高位移試驗
圖3-4.RCEβ轉植抑制TNFα誘導程式性自殺
圖3-5.PDTC抑制NF-kB的活化
3-5-4HCV感染的肝組織及能表達HCV核蛋白之肝癌細胞株檢測Fas,TNFR-I及TRAF3的表達正常
圖3-7.Fas,TNFR-I及TRAF3在HCV-感染的肝組織及HCV-轉植的HepG2細胞株上都正常的表達
討論
致謝
4.第三部:肝癌組織核因數kappaB的體質性活化
Constitutive
4-1中文摘要
4-2英文摘要
4-3引言
4-4材料及方法
4.4-1免疫組織切片染色
4.4-1a材料
表4-1研究病人基本資料
4.4-1b RelA及IkBα免疫組織切片染色
4.4-2蛋白質的電泳移動位移試驗(EMSA)及西方墨點雜交法
4.4-2a 材料
4.4-2b 核及細胞蛋白的碎取及定量
4.4-2c EMSA試驗
4.4-2d RelA,NFkB及IkBα西方墨點法
4.4-3IkBαmRNA的半定量
4.4-4統計分析
4-5結果
4.5-1肝癌組織RelA及IkBα核染色較強
圖4-1肝組織免疫染色
表4-2RelA及IkBα肝組織免疫染色在正常組,肝癌及非肝癌組織的差異
4.5-2肝癌組織NF-kB體質性表達
圖4-2病例A到F在EMSA檢查中腫瘤與非腫瘤之差異
4.5-3肝癌組織核蛋白RelA表達強而細胞質IkBα表達弱
圖4-3病例A到F西方墨點檢查中RelA在腫瘤與非腫瘤之差異
圖4-4病例A到F西方墨點檢查中IkBα在腫瘤與非腫瘤之差異
表4-3比較37對肝腫瘤與非腫瘤在EMSA中NF-kB與kB oligoduplex DNA結合強弱及NF-kB蛋白在西方墨點法之表達
圖4-5EMSA試驗中NF-kB的活性,以及在西方墨點法RelA與IkBα的表達在正常肝組織,腫瘤與非腫瘤之相對差異
4.5-3肝癌組織細胞質IkBα mRNA表達未減弱
4-6結論
5.文獻
6.近期著作
7.附件:第二部抽印本及編輯附加注解

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2. 鄭淑子(民81)。大學生性別角色取向、道德雙重標準和異性交往態度之發現。實踐學報,23,55-103。
3. 潘家慶(民72)。傳播內容與色情材料,中國論壇,16,(10),10-11。
4. 趙宏達(民88)。網路族你上癮了嗎?張老師月刊,260,129-130。
5. 楊淑萍(民84)。學校性教育的理念與實施,諮商與輔導,112,34-37。
6. 黃國彥(民71)。社會青年的性知識、態度、行為之初探,政大教育與心理研究,5,115-176。
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9. 張利中(民87)。大專學生於電子佈告欄(BBS)連線性學討論區所提性問題之研究,臺灣性學學刊,4,(2),36-49。
10. 林宇玲(民89)。解讀全球資訊網上的台灣女性網站:由網站論述表現看性別與科技之關係。婦女與兩性學刊,11,1-33。
11. 周月英(民84)。等待指令的感官之旅─色情光碟片中的女體,聯合文學,11,(4),105-108。
12. 李美枝(民85)。兩性關係的社會生物原型在傳統中國與今日台灣的表現型態。本土心理學研究,5,114-174。
13. 李美枝(民82)。兩性之間的喜歡、愛情與婚前性行為的容許度。中華心理學刊,2,(25),121-135。
14. 李美枝(民70)。性別特質問卷的編製及男女大學生四種性別特質類型在成就動機、婚姻、事業及性態度上的比較。中華心理學刊,1,(23),23-37。
15. 呂桂雲(民72)。台北市大專學生對婚前性行為的態度及經驗之調查與探討。實踐學報,14,1-27.
 
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