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系統識別號 U0026-2507201114305600
論文名稱(中文) 探討癌細胞中EGF所誘導IL-1β表現之轉錄調控
論文名稱(英文) Transcriptional regulation of IL-1β in EGF-treated cancer cells
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 99
學期 2
出版年 100
研究生(中文) 楊鎮鴻
研究生(英文) Jhen-Hong Yang
學號 s26981123
學位類別 碩士
語文別 中文
論文頁數 87頁
口試委員 指導教授-陳炳焜
口試委員-張文昌
口試委員-洪良宜
中文關鍵字 癌症  抗藥性 
英文關鍵字 cancer  drug resistance 
學科別分類
中文摘要 IL-1β為一種促發炎性細胞激素,與腫瘤形成有很大的相關性,可作為一個癌症進展的指標。此外,EGFR過度表現時與腫瘤生長及轉移也有很大的相關。在我們研究中發現有EGFR過度表現現象的人類子宮頸上皮細胞癌A431中,處理EGF之後,IL-1β基因與蛋白表現,有上升的情形。然而,在細胞中EGF是如何調控IL-1β基因表現的,仍不清楚。首先我們確認EGF是經由轉錄作用,而非影響IL-1β mRNA穩定度,進而誘導IL-1β基因表現。我們更利用Akt藥理性抑制劑LY294002與NF-κB藥理性抑制劑確認EGF經由Akt-NF-κB訊息傳遞路徑,來誘導IL-1β基因啟動區活性。接著利用免疫螢光染色法,確認EGF會活化Akt訊息傳遞路徑而誘導NF-κB (p65)的入核現象;下一步,由DNA親和沉澱實驗得知,EGF活化Akt路徑後,再促使NF-κB (p65)入核結合到IL-1β啟動區上的NF-κB結合位上,進而活化IL-1β啟動區的活性。此外,我們另外發現另一個轉錄因子ARNT也參與在EGF所誘導的IL-1β基因調控中。最後我們發現EGF可以藉由增加IL-1β,而降低了cisplatin對於癌細胞的毒殺作用,進而增加細胞的抗藥性。總結整篇研究得知在癌細胞中EGF藉由活化Akt- NF-κB 路徑而使IL-1β表現增加,進而影響化療藥物的抗藥性,因此IL-1β的表現量可作為評估藥物於癌症治療效用的重要指標。
英文摘要 IL-1β is the well-known cytokine that has been characterized as an indicator of several cancers, and it may affect the process of carcinogenesis. In addition, epidermal growth factor receptor (EGFR) is an important regulator of tumor growth and metastasis. We found that IL-1β gene and protein expression were induced by treating EGFR-overexpressed A431 cell with EGF. However, the mechanism involved in EGF-regulated IL-1β expression is not clarified in A431 cells. IL-1β was found to be induced by EGF which was mediated through the transcription activation, but not change of mRNA stability. The involvement of Akt and NF-κB signaling pathways in the EGF-induced IL-1β gene expression and promoter activity was ensured by treating cells with Akt and NF-κB inhibitors, LY294002 and Parthenolide, respectively. By Immunofluorescence staining assay, we found that EGF-stimulated nuclear transclocation of NF-κB (p65) was inhibited by pretreating cells with LY294002 and Parthenolide. Furthermore, by DNA affinity precipitation assay we also found that EGF increased the binding of NF-κB to NF-κB binding site of IL-1β promoter through activation of Akt pathway, and then activated IL-1β promoter activity. In addition, a transcription factor, ARNT, was participated in regulation of EGF-induced IL-1β gene expression. Furthermore, we found that EGF could regulate cancer cells resistance to cisplatin through the induction of IL-1β expression. These results reveal that up-regulation of IL-1β by EGF-activated Akt-NF-κB pathway in cancer cells can confer resistance to chemotherapy. The expression of IL-1β may become a biomarker to evaluate the successful cancer treatment.
論文目次 摘要 I
Abstract II
誌謝 III
目錄 IV
附圖目錄 VII
第一章 緒論 1
第一節 Interleukin-1β (IL-1β) 1
第二節 IL-1β與腫瘤形成的關係 3
第三節 IL-1β調控之機轉 4
第四節 NF-κB pathway 5
第五節 Epidermal Growth Factor (EGF) 6
第六節 Aryl hydrocarbon receptor translocator (ARNT) 7
第七節 Cisplatin 8
研究動機 9
第二章 實驗材料與方法 10
第一節 實驗材料來源 10
試劑藥品與耗材 10
抗體 16
第二節 實驗方法: 18
第三章 實驗結果 47
第一節 探討EGF處理之下對於IL-1β表現的影響 47
(一) EGF誘導IL-1β之基因表現 47
(二) EGF誘導IL-1β之蛋白表現 48
第二節 探討癌細胞中EGF誘導IL-1β 基因表現是透過何種訊息傳遞路徑..48
(一) ERK與JNK路徑沒有參與EGF所誘導IL-1β基因表現 49
(二) EGF經由Akt- NF-κ B訊息傳遞路徑而誘導IL-1β基因表現 49
(三) EGF活化Akt路徑而誘導NF-κ B蛋白入核表現 50
第三節 探討EGF對於IL-1β mRNA穩定度之影響 51
第四節 探討NF-κ B因EGF而活化是否結合至IL-1β啟動區 51
(一) EGF可促使NF-κ B蛋白結合至IL-1β啟動區之NF-κ B結合區 52
(二) EGF活化Akt路徑而誘導NF-κ B蛋白結合至IL-1β啟動區之NF-κB結合區 52
第五節 探討EGF處理之下對於IL-1β啟動區活性的影響 53
(一) EGF誘導IL-1β之轉錄活性 53
(二) Akt路徑與NF-κ B路徑參與EGF所誘導IL-1β之轉錄活性 53
(三) 探討 IL-1β啟動區上NF-κ B結合位對於EGF所誘導IL-1β之轉錄活性之重要性 54
第六節 探討ARNT調控IL-1β的基因表現 54
(一) ARNT knockdown抑制了EGF所誘導IL-1β 基因表現與啟動區活性 ………………………………………… 55
(二) ARNT 過度表現誘導IL-1β的啟動區活性 56
第七節 探討EGF誘導IL-1β表現是否影響其細胞的抗藥性 56
(一) EGF和IL-1β增加細胞對於cisplatin的抗藥性 56
(二) EGF誘導IL-1β表現,進而增加細胞對於cisplatin的抗藥性 57
第四章 討論 59
第五章 參考文獻 64
自述 87



附圖目錄
Figure 1. The effect of EGF on IL-1β expression…………………………73
Figure 2. Effect of SP600125 and Uo126 on EGF-induced expression of IL-1β gene………………………………………………………………………………. 74
Figure 3. Effect of LY294002 and Parthenolide on EGF-induced expression of IL-1β gene……………………………………………………………… 75
Figure 4. Inhibition of the AKt and NF-κB pathways attenuates EGF-induced IL-1β mRNA expression in TU183 and SCC25………………………………... 76
Figure 5. Involvement of Akt in EGF-induced NF-κB protein nuclear transcloction. ……………………………………………………………………. 77
Figure 6. Effect of EGF on IL-1β mRNA stability………………………78
Figure 7. The NF-κB bind to the IL-1β promoter in A431 cells…………79
Figure 8. Involvement of Akt and NF-κB in EGF-induced IL-1β promoter activity……………………………………………………………………………. 80
Figure 9. Effect of ARNT on EGF-induced IL-1β gene expression and promoter activity………………………………………………………………… 82
Figure 10. The effect of EGF and IL-1β on cisplatin-induced cytotoxicity in A431 cells………………………………………………………………………… 83
Figure 11. The effect of EGF-induced IL-1β expression on cisplatin-induced cytotoxicity in A431 cells……………………………………85
Figure 12. Up-regulation of IL-1β by EGF-activated Akt-NF-κB pathway in cancer cells can confer resistance to cisplatin…………………………………. 86
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