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系統識別號 U0026-0709201520410400
論文名稱(中文) 環氧化酶 2 以及丙酮酸脫氫激酶1 在表皮生長因子促進頭頸鱗狀癌轉移中扮演的角色
論文名稱(英文) The role of cyclooxygenase-2 and pyruvate dehydrogenase kinase 1 in epidermal growth factor-enhanced head and neck squamous cell carcinoma metastasis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 許晉源
研究生(英文) Jinn-Yuan Hsu
學號 s58981280
學位類別 博士
語文別 英文
論文頁數 151頁
口試委員 指導教授-張文昌
指導教授-陳炳焜
召集委員-賴明德
口試委員-王育民
口試委員-洪文俊
口試委員-呂增宏
口試委員-林琬琬
口試委員-許世賢
中文關鍵字 表皮生長因子受器  環氧化酶 2  轉移  纖維黏連蛋白  丙酮酸去氫激酶1  頭頸部鱗狀細胞癌 
英文關鍵字 EGFR  COX-2  metastasis  fibronectin  PDK1  HNSCC 
學科別分類
中文摘要 表皮生長因子受器的活化是造成許多癌症轉移的主要原因,其中也包含了頭頸鱗狀癌。發炎因子和代謝疾病已知跟癌症發生有關連,然而,發炎反應誘導環氧化酶 2 以及代謝酵素丙酮酸脫氫激酶1 參與在調控表皮生長因子,以及促進頭頸鱗狀癌轉移的功能上還不清楚。有趣的是,我們發現表皮生長因子誘導環氧化酶 2 以及丙酮酸脫氫激酶1 的表現主要是在頭頸鱗狀癌細胞。表皮生長因子刺激腫瘤細胞的轉型能力,可以經由降低氧化酶 2 或是丙酮酸脫氫激酶1表現而被抑制。但是,在環氧化酶 2 被降低的情況下,加入表皮生長因子以及前列腺素 E2 可以重新活化癌細胞轉型能力。經由降低環氧化酶 2或是丙酮酸脫氫激酶1 的表現,可以使得表皮生長因子所促進的癌細胞爬行以及侵犯能力被有效的抑制住。除此之外,經由降低環氧化酶 2 的表現而導致癌細胞爬行以及侵犯能力被抑制的狀況,則可以透過加入前列腺素 E2 而重新回復這些能力。當降低環氧化酶2或是丙酮酸脫氫激酶1的表現時,基質金屬蛋白酶 1、2、3、9 以及纖維黏連蛋白還有 Rac1/cdc42 的活化都會因此而被抑制。在降低環氧化酶2表現的癌細胞中加入前列腺素E2,被抑制的基質金屬蛋白酶以及纖維黏連蛋白還有Rac1/cdc42 都會被前列腺素E2活化。更進一步,當降低纖維黏連蛋白的表現會影響環氧化酶 2 促進頭頸鱗狀癌細胞和內皮細胞的黏附,以及腫瘤細胞轉移到肺部的現象。降低丙酮酸脫氫激酶1或是環氧化酶 2 的表現,一樣都會影響表皮生長因子促進頭頸鱗狀癌細胞和內皮細胞的黏附,以及腫瘤細胞轉移到肺部的現象。這些結果顯示,表皮生長因子誘導環氧化酶 2或是丙酮酸脫氫激酶1 的表現,進一步會透過纖維黏連蛋白的訊息路徑來促進頭頸鱗狀癌細胞的轉移。未來在治療表皮生長因子受器所誘導的頭頸鱗狀癌細胞轉移,也許可以透過降低環氧化酶 2或是丙酮酸脫氫激酶1的表現以及活性來達成。
英文摘要 Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in many cancers, such as head and neck squamous cell carcinoma (HNSCC). While it is well known that inflammatory factors and metabolic diseases have been associated with the development of cancer, the regulation and functional role of inflammation-triggered cyclooxygenase-2 (COX-2) and metabolic enzyme pyruvate dehydrogenase kinase 1 (PDK1) in EGF-enhanced HNSCC metastasis remain unclear. Interestingly, we found that EGF induced COX-2 and PDK1 expression mainly in HNSCC. The tumor cell transformation induced by EGF was repressed by either COX-2 or PDK1 knockdown. The repression by COX-2 knockdown was eliminated when cells were treated with EGF and prostaglandin E2 (PGE2). Either down-regulation or inhibition of COX-2 and PDK1 significantly blocked EGF-enhanced cell migration and invasion. In addition, PGE2 compensated for the reduction in migration and invasion in COX-2-knockdown cells. Either COX-2 or PDK1 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. The inhibitory effect of COX-2 depletion on MMPs and the fibronectin/Rac1/cdc42 axis were reversed by co-treatment with PGE2. Furthermore, depletion of fibronectin impeded the COX-2-enhanced binding of HNSCC cells to endothelial cells and tumor cell metastatic seeding of the lungs. Depletion of PDK1 also impeded the EGF-enhanced binding of HNSCC cells to endothelial cells and tumor cell metastatic seeding of the lungs, as well as COX-2 knockdown. These results demonstrate that EGF-induced COX-2 and PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. The inhibition of expression and activation of COX-2 and PDK1 would be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.
論文目次 Contents
Abstract in Chinese I
Abstract III
Acknowledgment V
Contents VI
Figure contents X
Abbreviations XII
Introduction 1
I. HNSCC cancer 1
A. Overview of HNSCC 1
B. Pathogenesis 3
C. Changes in signaling pathways 4
The EGFR pathway: 4
Other signaling pathways: 6
The p53 and Retinoblastoma (RB) pathways: 6
The transforming growth factor-β (TGFβ) pathway: 6
D. Invasion and Metastasis 7
E. Therapeutic implication 8
II. COX-2 9
A. Basic concept of COX-2 9
B. COX-2 and cancer 10
C. The possible role of COX-2 in HNSCC metastasis 11
III. PDK1 12
A. Basic concept of PDK1 12
B. The possible role of metabolic enzymes in cancer 13
C. The possible role of targeting metabolic enzymes in prevention of HNSCC metastasis. 14
IV. The correlation between inflammation, metabolic disease and cancer 16
V. Research significance of this study 18
Materials and Methods 19
Cell Culture 19
Immunofluorescence 20
Anchorage-independent soft agar growth assay 21
Migration and invasion assays 21
Transendothelial invasion assay 22
Western blotting 23
Reverse transcription–polymerase chain reaction 24
Knockdown experiments 25
Transfection with siRNA oligonucleotides 26
Plasmid transfection and luciferase assays 26
Cell adhesion assay 27
Tumor metastasis assay in an animal model 27
Statistical analysis 28
Results 29
Chapter I: 29
1. Induction of COX-2 expression and enhancement of anchorage-independent growth in EGF-treated HNSCC cells 29
2. EGF-promoted COX-2 regulates HNSCC migration and invasion 30
3. EGF-induced COX-2 activates the fibronectin/FAK/Rac1/cdc42 signaling axis 32
4. Depletion of fibronectin inhibits PGE2-induced tumor cell invasion and interaction with endothelial cells 35
5. PGE2-induced fibronectin expression promotes tumor invasion in vivo 36
6. EGF-primed HNSCC metastasis is inhibited in mice fed with a celecoxib diet. 37
Chapter II: 39
7. Induction of PDK1 expression and enhancement of anchorage-independent growth in EGF-treated HNSCC cells 39
8. EGF-induced PDK1 regulates HNSCC migration and invasion 41
9. EGF-induced PDK1 activates MMPs and fibronectin/FAK/Rac1/cdc42 signaling axis 41
10. Depletion of PDK1 inhibits EGF-induced tumor interaction with endothelial cells 42
11. EGF-induced PDK1 expression promotes tumor invasion in vivo 43
12. The possible signaling pathway between COX-2 and PDK1. 44
13. To study the mechanisms involved in the regulation of PDK1 promoter activity. 44
Discussion 47
References 62
Figures 89
Appendixes 149
Curriculum vitae 150
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