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系統識別號 U0026-1907201217140100
論文名稱(中文) IKK beta 促進 mTOR 訊息活化以增進肝癌和食道腺癌細胞增生和血管新生因子表現
論文名稱(英文) Upregulated mTOR Signaling through IKK-beta Increases Cell Proliferation and VEGF Production in Hepatocellular Carcinoma and Esophageal Adenocarcinoma
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 100
學期 2
出版年 101
研究生(中文) 顏家瑞
研究生(英文) Chia-Jui Yen
電子信箱 yencj@mail.ncku.edu.tw
學號 s98921042
學位類別 博士
語文別 英文
論文頁數 76頁
口試委員 指導教授-張定宗
指導教授-蔣輯武
口試委員-蘇五洲
口試委員-賴明德
口試委員-張俊彥
口試委員-陳立宗
中文關鍵字 IKKβ  TSC1  mTOR  血管新生  肝癌  B 型肝炎  X 蛋白質  食道腺癌  膽酸 
英文關鍵字 IKKβ  TSC1  mTOR  angiogenesis  hepatoma  hepatitis B virus  X protein  esophageal adenocarcinoma  bile acid 
學科別分類
中文摘要 發炎反應和人類癌症發生高度相關,但發炎引起之致癌機轉尚未完全清楚,腫瘤壞死因子 (TNFα) 是發炎反應中細胞產生的發炎細胞激素,在TNFα刺激下可以活化IKK激酶(IkB Kinases),這條訊息傳導路徑主導著細胞對發炎刺激的反應。IKK 複合體為活化NF-κB的主要蛋白激酶,可調控NF-κB所媒介之細胞生長、血管新生、發炎、腫瘤轉移等相關基因表現。TSC1 是一個已知的腫瘤抑制基因,不正常的TSC 表現,可引起tuberous sclerosis complex (TSC) 疾病;TSC1 同時也有負向調控mammalian targetofrapamycin (mTOR) 的功能,不正常的TSC1/mTOR訊息傳導活化已經被證實和癌症發生有關。mTOR可以磷酸化和活化它下游S6 Kinase,S6 Kinase 的磷酸化可以增加細胞蛋白質合成和細胞的增生,同時也和血管新生有關,這樣的表現是腫瘤形成的重要因素。在本論文中,我們嚐試探討發炎反應IKKβ 促進 mTOR 訊息活化以增進肝癌和食道腺癌細胞增生和血管新生因子表現的重要問題。第一部分,膽酸逆流可以造成食道發炎,長期發炎刺激是形成食道腺癌的重要致癌因子。我們的研究發現膽酸逆流刺激可以活化IKKβ,同時正向調控mammalian target of rapamycin (mTOR) 的功能,進而磷酸化和活化它下游S6 Kinase, S6 Kinase 的磷酸化可以增加食道腺癌細胞的增生。在Barrett’s 食道病人和食道腺癌病人檢體的免疫組化檢查也證實IKKβ蛋白和S6 Kinase的磷酸化表現程度呈現正相關。第二部分,B 型肝炎是引起肝癌的重要危險因子,由B型肝炎感染造成肝癌致病分子基因機制還不清楚。我們的研究發現B 型肝炎病毒的X蛋白可以調控IKK 複合體中之IKKβ活化,影響TSC1 蛋白的磷酸化,同時也有正向調控mammalian target of rapamycin (mTOR) 的功能,進而磷酸化和活化它下游S6 Kinase,S6 Kinase 的磷酸化可以增加肝癌細胞的增生,同時也和肝癌血管新生有關。這樣的研究成果可以與臨床結合,我們使用B型肝癌相關肝癌病人檢體的免疫組化檢查,發現IKKβ, TSC1 蛋白和S6 Kinase的磷酸化表現程度與肝癌病人臨床預後高度相關。我們研究也利用抑制IKKβ的小分子化合物 Bay11-7082 和抑制mTOR的小分子化合物 rapamycin進行測試,發現Bay 11-7082和rapamycin有抑制肝癌和食道腺癌細胞增生及血管新生因子製造的效果。我們的研究發現期望可發展成有效的分子標靶治療抗癌新方式,以突破目前在臨床肝癌病人和食道腺癌病人治療困境。
英文摘要 Accumulated evidence suggests that inflammation is associated with human tumors, but the underlying mechanism of tumorigenesis is not yet fully understood. TNFα is considered one of the most important factors involved in inflammation-mediated tumorigenesis, and the transcription factor NF-κB, a downstream signaling transducer of TNFα, has been implicated in oncogenesis by promoting expression of genes related to cell proliferation and survival. Activation of the inhibitor of nuclear factor κB (IκB) kinase (IKK) by TNFα phosphorylates IκBs and promotes degradation of IκBs, resulting in nuclear translocation of NF-κB and induction of NF-κB downstream genes. Tuberous sclerosis complex 1 (TSC1), a well-known tumor suppressor involved in the development of tuberous sclerosis, negatively regulates the mammalian target of rapamycin (mTOR) pathway by inhibiting Ras homolog enriched in brain (RHEB). Deregulation of the TSC/mTOR signaling pathway has been implicated in the development of cancer and the activation of ribosomal protein S6 kinase (S6K1) by mTOR was found to lead to increased cell proliferation and angiogenesis. Our study deals with two important inflammatory associated cancers development. Firstly, bile acid reflux could induce the esophagus inflammation and esophageal adenocarcinoma development. Our study found that the bile acid deregulated the TSC1/mTOR pathway through IKKβ signaling. We found that treatment of Barrett’s esophagus cells and esophageal adenocarcinoma cells with the IKKβ inhibitor Bay 11-7082 or the mTOR inhibitor rapamycin inhibited cell proliferation and in vitro transformation measured by the anchorage-independent growth assay. We next evaluated normal esophageal epithelium, Barrett’s esophagus lesions and tumor samples from patients with Barrett’s esophagus-associated esophageal adenocarcinoma and found a concomitant sustained expression of both, pIKKβ and pS6K1, in Barrett’s esophagus high-grade dysplasia and in esophageal adenocarcinoma. Our results indicate that bile acid may activate the mTOR pathway via IKKβ signaling, leading to Barrett’s esophagus and esophageal adenocarcinoma. Secondly, hepatitis B infection is highly associated with hepatoma development. However the truth oncogenic mechanism is still under study. We investigated whether HBx can modulate IKKβ to inactivate TSC1’s inhibition on mTOR so that it contributes to HCC development. We found that HBx modulated IKKβ/TSC1/mTOR signaling and up-regulated cell proliferation and VEGF production in hepatoma cells. Furthermore, we investigated the status of IKKβ/TSC1/mTOR signaling in specimens from HBV-associated human hepatomas, and analyzed the relationship between the status of IKK/TSC1/mTOR signaling and the prognosis of HCC patients. We conclude that IKKβ activates mTOR signaling through TSC1 suppression to contribute to one crucial mechanism underlying HBx-dependent pathogenesis of HCC. In conclusion, we demonstrate that activation of the IKKβ/mTOR pathway occurs concomitantly with increased cell proliferation and angiogenesis, which may associate with the progression of the hepatoma and esophageal adenocarcinoma. Blocking IKKβ or mTOR signaling with Bay 11-7082 or rapamycin, respectively, inhibits the cancer cell growth and VEGF-A production, suggesting that inhibitors of IKKβ or mTOR signaling may be useful as new therapeutics for the treatment of HBV-associated hepatoma and Barrett’s esophagus- associated esophageal adenocarcinoma.
論文目次 中文摘要 1
英文摘要 3
誌謝 5
Table contents 9
List of figures 10
Abbreviation list 11
Part 1 Bile Acid Exposure Upregulates TSC1/mTOR Pathway in Barrett’s Associated Esophageal Adenocarcinoma
Introduction 13
Materials and methods 16
Results 21
Discussion 26
Part 2 Hepatitis B virus X protein upregulates mTOR signaling through IKKß to increase cell proliferation and VEGF production in hepatocellular carcinoma
Introduction 29
Materials and methods 31
Results 36
Discussion 40
References 44
Tables 55
Figures 56
Curriculum Vitae 73
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