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研究生:伍珍妮
研究生(外文):Chen-Ni Wu
論文名稱:台灣欒樹胰蛋白酶抑制劑誘導 人類結直腸癌細胞(Colo320)凋亡之研究
論文名稱(外文):Induction of apoptosis by Koelreuteria formosana trypsin inhibitor in human colorectal carcinoma cell (Colo320)
指導教授:洪志宏洪志宏引用關係
指導教授(外文):Chih-Hung Hung
學位類別:碩士
校院名稱:元培科技大學
系所名稱:醫學檢驗生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
畢業學年度:101
語文別:中文
論文頁數:62
中文關鍵詞:台灣欒樹細胞凋亡大腸癌胰蛋白酶抑制劑Kunitz-type細胞凋亡
外文關鍵詞:Koelreuteria formosanacolorectal carcinoma celltrypsin inhibitorKunitz-typeapoptosis
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在台灣,大腸癌一直位居癌症死亡原因第三位。目前已有許多研究指出胰蛋白酶抑制劑與癌細胞產生凋亡有很大的關聯,所以尋找和利用胰蛋白酶抑制劑對癌細胞的抑制作用具有很大的研究目的。在本篇論文中,主要探討台灣欒樹(Koelreuteria formosana)種子所萃取出的胰蛋白酶抑制劑(Koelreuteria formosana trypsin inhibitor),簡稱KFTI,誘導人類結直腸癌細胞(Colo320)凋亡的產生。首先從台灣欒樹中純化出KFTI,純化過程使用硫酸銨分割,經過透析及活性分析,得知其活性介於硫酸銨分割70-100%之間,接著將其活性的部分通過Sephadex G-50管柱、DEAE-cellulose 52 管柱和親和性色層分析管柱(Affinity chromatography column) 純化,最後純化出的胰蛋白酶抑制劑以SDS-PAGE分析,得知其分子量約19 kDa,由12.3 kDa和6.7 kD兩個次單位以雙硫鍵連接所組成,屬於Kunitz-type的抑制劑。進一步研究KFTI的蛋白質特性。以100℃高溫處理10分鐘,仍具有77%的活性,可得知KFTI對熱具有非常高的穩定性;在pH值3.0-10.0範圍內,結果顯示KFTI抑制胰蛋白酶的活性不受pH值的影響而有所改變;以不同濃度的SDS處理10分鐘,測量其殘留抑制胰蛋白酶的活性剩下17%活性,可見結構對SDS非常不穩定;以不同濃度的DTT處理10分鐘,測量其殘留抑制胰蛋白酶的活性只剩不到10%,可知雙硫鍵對其結構的穩定度有絕對的重要性。之後利用MTT assay偵測KFTI對大腸結直腸癌細胞(Colo320)生長之影響,發現隨著KFTI的濃度及時間的增加,細胞的存活率逐漸減少,濃度在濃度在20μM時,細胞存活率下降至72.2%;且在72小時後,可以使細胞存活率下降至70%。之後利用流式細胞儀以annexin V來檢測apoptosis,由結果得知在48及72小時15μM KFTI處理的細胞,M2(凋亡細胞)有明顯上升,代表KFTI在15μM就有使Coko320 cells產生細胞凋亡的能力。以西方墨點法檢測apoptosis相關性蛋白caspase-3、caspase-9、Bcl-2的表現量,結果發現細胞逐漸走向細胞凋亡。
Colorectal cancer has persistently been the third most common cancer related cause of death in Taiwan. Research today has suggested a strong association between protease inhibitor and the apoptosis of tumor cells, and identifying protease inhibitor for the application of tumor growth inhibition possesses great research value. The primary objective of this research focuses on the Koelreuteria formosana trypsin inhibitor (KFTI) extracted from Koelreuteria formosana and its ability to induce apoptosis in human colorectal cell (Colo320). KFTI was first extracted from Koelreuteria formosana and then purified using ammonia sulfate. Activity analysis revealed that protein with the desired activity is salted by ammonia sulfate at approximately 70-100%. The active region was then passed through a Sephadex G-50, DEAE-cellulose 52 and affinity chromatography column. The final protease inhibitor obtained from the purifying process was then analyzed using SDS-PAGE. The inhibitor is of Kunitz-type and its molecular weight is approximately 19 kDa, which comprises of a 12.3 kD and 6.7 kD subunit linked by disulfide bond. The protein properties of KFTI were further analyzed. We discovered that KFTI is heat resistant as it is able to retain 77% of its activity after 10 minutes of high temperature (100°C) processing. We also processed the KFTI protease inhibitor with pH value ranging from 3.0-10.0 and its activity is unaffected by change in pH value. Nevertheless, only 17% activity was retained after being processed in SDS of different concentration for 10 minutes, and we conclude that its structure is very unstable to SDS. The protein was also processed in DTT of different concentration for 10 minutes and less than 10% of its protease inhibitor activity was retained after the experiment. From this result, we can tell that the disulfide bond plays a very important role in maintaining its structural stability. We then used MTT assay to evaluate KFTI’s influence on the growth of colorectal cancer cells (Colo320). We discovered that the survival rate of the cancer cells decreases with an increase in KFTI concentration and exposure time. Cell survival rate decreased to 72.2%, and 70% +72h at a concentration of 20μM. Cell apoptosis was then evaluated using flow cytometry with annexin V and the result revealed that cells processed by KFTI at a concentration of 15μM for 48 and 72 hours have and increased rate of M2 (apoptosis) and we therefore conclude that KFTI is able to induce apoptosis of Colo320 cells with a mere 15μM concentration. Western blot was used to evaluate the association of apoptosis and the relative proteins such as caspase-3, caspase-9, Bcl-2. The test also revealed that the cells were driven towards apoptosis.
致謝………………………………………………………………………………I
中文摘要………………………………………………………………..............II
英文摘要……………………………………………………………………….IV
縮寫表………………………………………………………………………….VI
目錄…………………………………………………………………………..VIII
圖目錄………………………………………………………………………….XI
附圖目錄………………………………………………………………………XII
第一章 緒論……………………………………………………………………1
1.1植物蛋白酶抑制劑介紹 …1
1.2台灣欒樹胰蛋白酶介紹 3
1.3大腸癌介紹 4
1.3.1大腸癌 4
1.3.2大腸癌的症狀 4
1.3.3大腸癌的分期 5
1.3.4大腸癌的治療 7
1.3.5大腸癌的預防 8
1.4細胞凋亡 9
1.5論文研究方向 12
第二章 研究材料與方法……………………………………………………..13
2.1親和性色層分析管柱之製備 13
2.2 KFTI之萃取 14
2.3胰蛋白酶抑制劑活性測定法 16
2.4蛋白質濃度測定 17
2.4.1試劑 17
2.4.2步驟 17
2.5 SDS-聚丙烯醯胺膠體電泳 18
2.5.1溶液配製 18
2.5.2 SDS-聚丙烯醯胺膠體電泳 18
2.5.3 Coomassie Brilliant Blue R-250染色與退染 19
2.6 KFTI對胰蛋白酶抑制活性的穩定度 19
2.6.1溫度的影響 19
2.6.2 pH的影響 20
2.6.3 SDS的影響 20
2.6.4 DTT的影響 20
2.7細胞培養 21
2.8 MTT assay 21
2.9 Annexin V檢測Apoptosis 22
2.10西方轉漬法 23
2.10.1蛋白萃取 23
2.10.2西方轉漬 23
2.11統計分析 24
第三章 研究結果……………………………………………………..............25
3.1台灣欒樹胰蛋白酶抑制劑(KFTI)之純化 25
3.2 KFTI對胰蛋白酶抑制劑活性的穩定度 26
3.3 KFTI對Colo320 cells生長之影響-MTT assay 27
3.4以Annexin V檢測Apoptpsis 27
3.5 KFTI處理Colo320 cells細胞凋亡相關性蛋白質表現量的影響 28
第四章 結論與討論…………………………………………………………..30
第五章 圖表說明……………………………………………………………..34
參考文獻………………………………………………………………………49

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二、中文部分
1. 洪志宏,董陳峰,陳韻帆 ,周孝怡,黃靖晏,王海龍,洋紫荊(Bauhinia purpurea)種子中胰蛋白酶抑制劑之純化及其特性, 元培學報第十七期民國 99 年12 月17-28
2. 行政院衛生署,民國101年主要死因分析,2013
3. 陳月文,「看見台灣大樹」,遠流,2008

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