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系統識別號 U0026-0809201519554300
論文名稱(中文) 表皮生長因子透過環氧化合酶2所誘發血管生成因子樣蛋白4表現並促進頭頸癌細胞的轉移
論文名稱(英文) EGF-induced COX-2 enhances ANGPTL4 expression and promotes HNSCC metastasis
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 103
學期 2
出版年 104
研究生(中文) 吳沛庭
研究生(英文) Pei-Ting Wu
學號 s26021062
學位類別 碩士
語文別 英文
論文頁數 64頁
口試委員 指導教授-陳炳焜
口試委員-洪良宜
口試委員-張偉嶠
中文關鍵字 頭頸癌  表皮生長因子  血管生成因子樣蛋白4  胞外調節激酶  環氧化合酶2  前列腺素E2 
英文關鍵字 Head and neck cancer  ANGPTL4  ERK  COX-2  PGE2 
學科別分類
中文摘要 表皮生長因子受器的過度表現在頭頸癌細胞是種常見的現象,表皮生長因子受器的活化能促進頭頸癌細胞的惡性轉移以及降低病人的生存率。在我們先前的研究中,我們發現表皮生長因子所誘發的血管生成因子樣蛋白4的表現參與在頭頸癌細胞的轉移。然而,我們卻不了解表皮生長因子是透過哪些分子機制去調控血管生成因子樣蛋白4的表現以及這個現象在頭頸癌細胞中扮演著什麼樣的角色。在本篇研究中,我們發現了表皮生長因子透過細胞外調節激酶調控血管生成樣蛋白4的表現並非透過核轉錄因子κB訊息傳遞。此外,環氧化合酶2的表現量也會被表皮生長因子所誘發。我們發現了使用希樂葆抑制了環氧化合酶2的活性或是將其基因剔除都可以抑制表皮生長因子誘導的血管生成因子樣蛋白4的表現。前列腺素E2可隨著時間的增加而顯著增加血管生成因子樣蛋白4訊息RNA及蛋白質的表現。抑制細胞外調節激酶的活性明顯地阻斷了前列腺素E2所誘發血管生成因子樣蛋白4的表現。此外,血管生成因子樣蛋白4啟動子若含有過氧化物酶體增殖物活化受體反應序列,則前列腺素E2可以活化此啟動子。總結,我們看到了表皮生長因子透過細胞外調節激酶以及環氧化合酶2訊息傳遞路徑去調控血管生成因子樣蛋白4的表現。細胞外調節激酶和過氧化物酶體增殖物活化受體的活化對於前列腺素E2誘導血管生成因子樣蛋白4表現量增加可能扮演一個重要的因素。在功能上,環氧化合酶2調控血管生成因子樣蛋白4在頭頸癌細胞中扮演什麼樣的角色是需要更加確認及證實。
英文摘要 Overexpression of EGFR is a common phenomenon in head and neck cancer squamous cancer cell (HNSCC). Activation of EGFR signaling pathway contributes to HNSCC metastasis and reduces patients’ survival. In our previous studies we found that EGF-induced angiopoietin-like 4 (ANGPTL4) was involved in tumor metastasis. However, the mechanisms of EGF-induced ANGPTL4 and the functional roles of ANGPTL4 in HNSCC metastasis remain unclear. In this study, we found that EGF activated ERK, but not NF-κB signaling pathway was involved in the regulation of ANGPTL4 expression. In addition, the expression of COX-2 was also induced in cells treated with EGF. Furthermore, we found that either inhibition of COX-2 activity using celecoxib or knockdown of COX-2 in cells inhibited EGF-induced ANGPTL4 expression. PGE2 significantly induced the expression of ANGPTL4 mRNA and protein in time-dependent manners. Inhibition of ERK activation dramatically blocked PGE2-induced ANGPTL4 mRNA expression. In addition, ANGPTL4 promoter containing with PPARE was enhanced by PGE2. In summary, we found that EGF-induced ANGPTL4 expression via ERK and COX-2 signaling pathways. Activation of ERK and the involvement of PPAR signaling may be essential for PGE2 enhanced ANGPTL4 expression. The functional roles of ANGPTL4 regulated by COX-2 in HNSCC metastasis will be further studied.
論文目次 Abstract in Chinese ....i
Abstract ....ii
Acknowledge ....iii
Introduction....1
Head and neck squamous cell carcinoma ....1
1.1 The epidemiology of head and neck squamous cell carcinoma ....1
1.2 The metastasis of HNSCC ....
1.3 Treatment of head and neck squamous cell carcinoma.... 1
The correlation of EGF and HNSCC metastasis....2
2.1 The biology function of EGFR in HNSCC ....2
2.2 EGFR promotes HNSCC distant organ metastasis ....3
Inflammation promotes HNSCC progression ....4
3.1 Inflammation and cancer....4
3.2 Inflammatory cytokines promote cancer metastasis....4
Angiopoietin-like 4 (ANGPTL4)....5
4.1 The functional domain of ANGPTL4....5
4.2 The regulation of ANGPTL4 in cellular context ....6
Materials and Methods....8
Results ....12
EGF-induced COX-2 expression is related to ANGPTL4 secretion in HNSCC ....12
EGF induces ANGPTL4 expression through COX-2 signaling in HNSCC ....12
PGE2 enhances ANGPTL4 expression ....13
ERK signaling is involved in EGF-regulated ANGPTL4 ....13
ANGPTL4 expression is up-regulated in metastatic HNSCC....15
Discussion ....16
Reference ....20

Figure 1. EGF Induces ANGPTL4 and COX-2 mRNA and protein levels In time-dependent manners in HNSCC.....30
Figure 2. EGF-induced COX-2 up-regulation mediates ANGPTL4 expression in HNSCC. ....32
Figure 3. PGE2, an enzymatic product of COX-2, enhanced ANGPTL4 expression in HNSCC. ....35
Figure 4. EGF mediates ANGPTL4 and COX-2 expression through ERK, not through NF-κB to regulate ANGPTL4 expression.....37
Figure 5. PGE2 needs ERK activation to regulate ANGPTL4 expression, and PPARδ is not involved in PGE2-regulated ANGPTL4 expression in HNSCC. ....42
Figure 6. ANGPTL4 gene up-regulation in HNSCC metastatic tissue sample....46

appendix Fig 1. EGF induces ANGPTL4 mRNA expression in HNSCC ..48
appendix Fig 2. EGF-induces ANGPTL4 mRNA expression is blocked by ERK, JNK inhibitor ....49
appendix Fig 3.The map of ANPTL4 promoter with or without PPARE....51

Table 1. The clone ID and target sequence of shRNA lentiviral particles from National RNAi Core Facility Platform. ....52
Table 2. The reagents and condition of Site-directed mutagenesis. ....52
Table 3. The sequence of RNA interference.....53
Table 4. The antibody dilutions. ....53
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