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研究生:王政祺
研究生(外文):Cheng-Chi Wang
論文名稱:以小鼠模型探討脂肪酸誘導微小核糖核酸-378於大腸癌治療之效果
論文名稱(外文):To discuss the treatment of fatty acid induced expression of miR-378 by mouse model.
指導教授:翁文慧
指導教授(外文):Wen-Hui Weng
口試委員:潘同明馮思中吳慧中翁文慧
口試日期:2016-07-24
學位類別:碩士
校院名稱:國立臺北科技大學
系所名稱:生化與生醫工程研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
畢業學年度:104
語文別:中文
中文關鍵詞:皮下生長因子受體抑制劑魚油微核糖核酸-378大腸直腸癌
外文關鍵詞:Fatty acidCetuximabmiR-378Colorectal Cancer (CRC)
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先前研究中已經證實在KRAS和BRAF基因突變型大腸癌細胞中微小核糖核酸-378的低表達,但在野生型大腸癌細胞中卻不見此情況。在先前實驗中我們已成功將微小核糖核酸-378轉染至人類大腸直腸癌細胞中,並證實在突變型大腸癌細胞中恢復微小核糖核酸-378的表達,有助於提升大腸癌標靶藥物的治療效果。此外,我們也證實了魚油可調控PGC-1 β基因3’端之第一個內顯子上的微小核糖核酸-378使其表現量增加。於此實驗,計劃將先前體外實驗研究整合後,藉由動物實驗進一步探討微小核糖核酸-378於生物體內的角色與其價值。其次,將魚油與標靶藥物之建議使用劑量用於動物體上,加以確定魚油可刺激PGC-1 β基因,使微小核糖核酸-378表現量提升,進而改善標靶藥物之治療效果,以利此藥物使用於臨床醫療上。此實驗中,我們將大腸癌細胞轉植小鼠體內,建立大腸直腸癌小鼠模型,餵食魚油以刺激提升小鼠體內微小核糖核酸-378表現量,再藉由標靶藥物使用,觀察實驗組和對照組中標靶藥物敏感性是否提升,及觀察小鼠體內腫瘤生長情況。實驗結果顯示轉染微小核糖核酸-378至大腸癌細胞72小時後,p-eIF2蛋白表現量有明顯提升。在動物實驗中我們也觀察到,KRAS和BRAF突變型的小鼠模型中,餵食魚油可改善原本標靶藥物治療無效的情況,並減緩腫瘤生長速度,達抑治療癌症的效果。此結果在臨床上將可改善將近40%以上原本無法以標靶藥物治療之KRAS或BRAF突變型大腸癌病患之治療效果,魚油配合標靶藥物使用可改善傳統治療方式,也可對病情得到更好的控制。
In previous study, we have showed that the expression of microRNA-378 (miR-378) in KRAS and BRAF are low in mutant colorectal cancer (CRC), but not in wild type CRC. Moreover, we also successfully transfected miR-378 into mutated CRC cells. Our data demonstrated that increase expression level of miR-378 in mutant CRC cells could restore the sensitivity of target drug. In addition, miR-378 located on 3’ end of PGC-1β gene and miR-378 expression level could be enhanced via simulated PGC-1β gene by using EPA. Herein, we conducted in vivo test based on our previous study, to further understand the role of miR-378 in living organism and the value of clinical treatment applications. Next, we referred to the recommended dose of EPA, combined with target drug in mouse model for further clinical therapeutic application and proved the expression of miR-378 could be enhanced by EPA. Finally, we detected cells response rate to the target drug, and monitor tumor progression. We use western blotting to detect the expression of p-eIF2. The results demonstrated that expression level of p-eIF2 could be increased via transfecting of miR-378. In animal experiment, we observed that sensitivity of the target drug could be improved by using EPA, and inhibit tumor growth. We expect the result will provide more than 40% treatment benefit of CRC patients, whose tumors contain with mutant KRAS or BRAF genes were considered resistant to the target drug and only can receive conventional therapies and it will provide a great helpful to clinical treatments.
摘要 i
ABSTRACT ii
致謝 iii
表目錄 vii
圖目錄 viii
第一章 導論 1
1.1 大腸癌介紹 1
1.1.1 大腸癌的分子基因突變過程 1
1.1.2 大腸癌的發生率與死亡率 2
1.1.3 大腸癌的標靶治療與早期診斷 3
1.1.4 免疫治療 (Immunotherapy) 6
1.2 微小核糖核酸-378 (mircoRNA-378, miR-378) 7
1.2.1 微小核糖核酸-378的形成 7
1.2.2 微小核糖核酸-378與癌症的關係 10
1.2.3 微小核糖核酸-378與MAPK pathway之關係 12
1.3 不飽和脂肪酸 (Unsaturated fatty acid) 13
1.3.1 脂肪酸介紹 13
1.3.2 魚油EPA 14
1.3.3 魚油EPA誘導PGC-1β與miR-378共同表達之關係 15
1.4 真核起始因子2 (Eukaryotic Initiation Factor 2, eIF2) 16
1.4.1 真核起始因子2在生物體內的調控 16
1.4.2 eIF2磷酸化與MAPK pathway的關係 17
1.4.3 EPA, miR-378與eIF2關係探討 18
第二章 研究動機與目標 19
第三章 材料與方法 21
3.1 細胞培養 21
3.1.1 大腸直腸癌細胞株選用 21
3.1.2 細胞培養試劑 21
3.1.3 細胞培養基配置 22
3.1.3 細胞解凍 22
3.1.4 細胞培養與繼代 22
3.1.5 細胞凍存 23
3.1.6 細胞種植 23
3.2 eIF2和p- eIF2蛋白質表現量之分析 24
3.2.1 實驗藥劑 24
3.2.2 蛋白質萃取 24
3.2.3 標準蛋白曲線繪製與BCA蛋白質抑制劑定量測定 25
3.2.4 西方墨點法 25
3.2.4.1 實驗原理 25
3.2.4.2 實驗流程 26
3.2.5 EPA與大腸癌細胞共同培養之eIF2和eIF2蛋白磷酸化表現量分析 27
3.2.5.1 實驗目的 27
3.2.5.2 材料與試劑 27
3.2.5.3 實驗方法 28
3.3 建立大腸癌小鼠模型及觀察腫瘤生長速度 29
3.3.1 實驗目的 29
3.3.2 材料與試劑 29
3.3.3 細胞準備 29
3.3.4 老鼠準備 30
3.3.5 大腸直腸癌小鼠模型建立 30
3.5 微核糖核酸-378轉染 (Transfection) 30
3.5.1 實驗原理 30
3.5.2 實驗試劑 31
3.5.3 實驗方法 31
3.6 統計方法 31
第四章 實驗結果 32
4.1 大腸癌小鼠模型建立 32
4.1.1小鼠模型施打藥物後腫瘤生長速度 32
4.2 EPA培養大腸癌細胞株對eIF2與p-eIF2之蛋白表現量 33
4.3 miR-378轉染大腸癌細胞培養對eIF2與p-eIF2之蛋白表現 35
第五章 討論 37
5.1 大腸癌小鼠模型給予藥物後腫瘤生長速度 37
5.2 大腸癌細胞株轉染miR-378後eIF2蛋白磷酸化表現差異與訊息傳遞之關係 37
5.3 脂肪酸誘導miR-378表達提升與細胞生長之關係 38
5.4 大腸癌細胞株與EPA培養後eIF2蛋白磷酸化表現差異 39
5.5 未來發展 40
參考文獻 42
附錄一 51
附錄二 52
附錄三 53
附錄四 54
附錄五 55
附錄六 56
附錄七 成果發表 57
附錄七 成果發表 58
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