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研究生:彭文麗
研究生(外文):Wei-Li Peng
論文名稱:上皮生長因子與其訊號傳遞抑制劑對人結直腸癌細胞程式化凋亡作用的調控
論文名稱(外文):Regulations of Apoptosis by Epidermal Growth Factor and Its Signal Transduction Inhibitors in Human Colorectal Cancer Cells
指導教授:趙振瑞趙振瑞引用關係
指導教授(外文):Jane C-J Chao, Ph. D.
學位類別:碩士
校院名稱:台北醫學院
系所名稱:保健營養學研究所
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:101
中文關鍵詞:上皮生長因子p21p53caspase-3人類結直腸癌細胞上皮生長因子抗體tyrphostin 51
外文關鍵詞:Key words: epidermal growth factorp21p53caspase-3human colorectal adenocarcinoma cellsEGF antibodytyrphostin 51
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摘 要
上皮生長因子 (epidermal growth factor; EGF) 可與細胞表面的上皮生長因子接受器結合,調控正常與腫瘤腸細胞的增殖作用。本研究之目的乃在探討上皮生長因子及其訊號傳遞抑制劑,對於人類結直腸癌細胞之程式化凋亡作用及其相關蛋白的影響。將人類結直腸癌細胞 (SW480) 培養於含有90% Leibovitz’s L-15/10%胎牛血清,使其生長至90%滿後,轉換成不含血清的基本培養液培養24小時。之後分別加入0.06% dimethyl sulfoxide (DMSO)、225 ng/mL EGF、225 ng/mL EGF + 2.5 g/mL EGF antibody或225 ng/mL EGF + 215 ng/mL tyrphostin 51 (上皮生長因子受器酪胺酸激酉每 抑制劑) 至細胞培養 液。由於tyrphostin 51需溶解於DMSO,所以其餘各組需同時加入等量的DMSO,以校正此因子。持續培養48小時後,收集細胞及培養液,每一組皆為七重複試驗 (n=7)。結果顯示添加EGF組細胞內EGF含量為DMSO組之418%;而EGF + EGF antibody 組和EGF + tyrphostin 51組皆明顯高於EGF組 (p < 0.05);EGF組培養液內EGF含量明顯高於DMSO組 (p < 0.05);而EGF組、EGF + EGF antibody組與EGF + tyrphostin 51組無明顯差異。活化型上皮生長因子受器
I
的表現於EGF組為DMSO組之183%;而EGF + EGF antibody組與EGF + tyrphostin 51組則分別為EGF組之36%與79%。觀察細胞程式化凋亡的結果,發現於12小時,EGF組與DMSO組之apoptotic cells數目無明顯差別。EGF + EGF antibody組與EGF + tyrphostin 51組之apoptotic cells數目在12小時,明顯比EGF組少;而EGF + EGF antibody組與EGF + tyrphostin 51組比較在12小時,並無明顯差別。此外,p53蛋白的表現於EGF組為DMSO組之102%,而EGF + EGF antibody組與EGF + tyrphostin 51組分別為EGF組之97%與83%;p21蛋白的表現於EGF組為DMSO組之115%,而EGF + EGF antibody組與EGF + tyrphostin 51組分別為EGF組之5%與51%。Caspase-3酵素的表現於EGF組為DMSO組之139%,而EGF + EGF antibody與EGF + tyrphostin 51組分別為EGF組之124%與133%。因此,在高濃度EGF (225 ng/mL) 下,會促進活化型上皮生長因子受器的表現,進而誘導caspase-3表現,若再添加EGF訊號傳遞抑制劑,則會降低活化型上皮生長因子受器、p53與p21蛋白的表現,並抑制apoptosis的進行,但caspase-3的表現反而會增加。

ABSTRACT
Epidermal growth factor (EGF) has been considered to regulate the
proliferation of normal and tumor intestinal cells through the EGF receptor (EGFR) on the cell surface. The study was to investigate the effects of EGF and its signal transduction inhibitors on apoptosis and its related proteins in human colorectal cancer cells. Human colorectal adenocarcinoma cells (SW480) were grown in 90% Leibovitz’s L-15 medium with 10% fetal bovine serum until 90% confluency, and switched to serum-free medium for 24 h. Cells (n = 7/group) were treated with 0.06% dimethyl sulfoxide (DMSO), 225 ng/mL EGF in 0.06% DMSO, 225 ng/mL EGF + 2.5 g/mL EGF antibody in 0.06% DMSO, or 225 ng/ml EGF + 215 ng/mL tyrphostin 51 (a tyrosine kinase blocker of EGFR) in 0.06% DMSO. Cells and media were collected after 48-h incubation. The results showed that cellular EGF contents in the EGF group were 418% of the DMSO group. Whereas, EGF contents in SW 480 cells were higher in the EGF + EGF antibody and EGF + tyrphostin 51 groups than those in the EGF groups (p < 0.05). The level of EGF in
III
the medium of the EGF group was higher than that of the DMSO group (p < 0.05). However, there was no significant difference among the EGF, EGF + EGF antibody and EGF + tyrphostin 51 groups. The expression of phosphorylated EGFR in the EGF group was 183% of the DMSO group. Phosphorylated EGFR in the EGF + EGF antibody and EGF + tyrphostin 51 groups was 36% and 79% of the EGF group, respectively. In addition, the expression of p53 protein in the EGF group was 102% of the DMSO group, and that in the EGF + EGF antibody and EGF + tyrphostin 51 groups was 97% and 83% of the EGF group, respectively. The expression of p21 protein in the EGF group was 115% of the DMSO group, and that in the EGF + EGF antibody and EGF + tyrphostin 51 groups was 5% and 51% of the EGF group, respectively. However, the expression of caspase-3 enzyme in the EGF group was 139% of the DMSO group, and that in the EGF + EGF antibody and EGF + tyrphostin 51 groups was 124% and 133% of the EGF group, respectively. Therefore, high concentration of EGF (225 ng/mL) could stimulate activated EGFR expression, and further induce caspase-3 expression. After the addition of signal transduction inhibitor
IV
of EGF, the expression of activated EGFR, p53 and p21 proteins was decreased, and apoptosis was inhibited, but the expression of caspase-3 was elevated.

目 錄
頁數
中文摘要 I
英文摘要 III
致謝                           VI
目錄 VII
表目次 X
圖目次 XII 第一章 緒論 1
第二章 文 獻 回 顧 2
第一節 造成腫瘤的可能原因 2
第二節 上皮生長因子的特性 4
第三節 上皮生長因子的訊號傳遞路徑 6
第四節 Tyrphostin 51的特性 10
第五節 細胞之程式化凋亡 (Apoptosis) 12
第六節 p53蛋白 15
第七節 Caspases酵素 21
第三章 材料及方法 26
VII
第一節 試劑 26
第二節 細胞培養 32
第三節 實驗設計 33
第四節 細胞計數 34
第五節 細胞及培養液中EGF含量 35
第六節 十二基硫酸鈉電泳法 (SDS-PAGE) 與西方墨點法
(Western blotting) 定量活化型EGFR蛋白含量 36
第七節 螢光顯影偵測apoptosis 38
第八節 十二基硫酸鈉電泳法 (SDS-PAGE) 與西方墨點法
(Western blotting) 定量p53、p21及caspase-3蛋白含量 40
第九節 統計分析 42
第四章 結果 43
第一節 上皮生長因子訊號傳遞抑制劑對SW480細胞及培養
液中EGF含量的影響 43
第二節 上皮生長因子訊號傳遞抑制劑對SW480細胞中EGFR
表現的影響 46
第三節 上皮生長因子訊號傳遞抑制劑對SW480細胞程式化
凋亡作用的影響 50
VIII
第四節 上皮生長因子訊號傳遞抑制劑對SW480細胞中p53
蛋白表現的影響 52
第五節 上皮生長因子訊號傳遞抑制劑對SW480細胞中p21
蛋白表現的影響 56
第六節 上皮生長因子訊號傳遞抑制劑對SW480細胞中
caspase-3酵素表現的影響 60
第五章 討論 63
第六章 結論 72
第七章 參考文獻 73
附錄A. EGF ELISA 88
附錄 B. Preparing Leibovitz’s L-15 Medium (1x liquid medium) 90
附錄 C. Bio-Rad DC Protein Assay 91
附錄 D. Brief Protocol of SDS-PAGE (Mini-gel) 93
附錄 E. Recipes for SDS-Polyacrylamide Gels 95
附錄 F. Western Blotting 97
附錄 G. ECL Western Blotting Analysis System 100
IX
圖目次
頁數
圖一 造成腫瘤的原因 3
圖二 上皮生長因子訊號傳遞路徑 8
圖三 細胞程式化凋亡及壞死之差異性 14
圖四 p53蛋白結構 19
圖五 細胞週期 20
圖六 細胞程式化凋亡訊號傳遞路徑 24
圖七 Fas訊號傳遞路徑 25
圖八 Annexin/phosphatidyl serine在早期細胞程式化凋亡的
變化 39
圖九之一 細胞內EGF含量 44
圖九之二 培養液中EGF含量 45
圖十 磷酸化EGFR蛋白的表現 47
圖十一 磷酸化EGFR蛋白的定量 48
圖十二 螢光顯微鏡觀察程式化凋亡細胞 51
圖十三 活化型p53蛋白的表現 53
X
圖十四 活化型p53蛋白的定量 54
圖十五 活化型p21蛋白的表現 57
圖十六 活化型p21蛋白的定量 58
圖十七 pro-caspase-3酵素的表現 61
圖十八 pro-caspase-3酵素的定量 62
圖十九 Ras-MAP路徑 70
圖二十 轉錄訊號傳遞和活化因子路徑 71
XI

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