臺灣博碩士論文加值系統

在台灣，大腸直腸癌是最常見的惡性腫瘤之一。臨床研究發現，40%的病人有KRAS或BRAF基因產生突變，多對表皮生長因子受器抗體–爾必得舒的治療不具明顯效果。本實驗室先前研究發現在KRAS或BRAF基因突變的大腸直腸癌細胞株中，當微型核醣核酸-378表達量提高，可促使表皮生長因子受器抗體對癌症細胞的毒殺性效果獲得改善。PGC-1β基因調控細胞內脂質代謝，而微型核醣核酸-378前驅體序列則座落於其第一個內涵子中。因此吾等假設，利用脂肪酸培養細胞可能誘導微型核醣核酸-378的表現量提升，可進而改善表皮生長因子受器抗體對細胞的療效。本研究藉由三株KRAS ( HCT 116, SW 480)或BRAF ( HT 29)突變型大腸直腸癌細胞株培養於飽和脂肪酸中的十二烷酸（月桂酸）培養基中，發現月桂酸確實可誘導微型核醣核酸-378表現量提升於大腸直腸癌中；且將細胞進ㄧ步施以表皮生長因子受器抗體作用，其結果更證實均可大幅改善此標靶藥物對KRAS或BRAF突變型癌症細胞的療效（p < 0.05），並降低ERK1/2蛋白質表現量，隨之可抑制細胞增生及促進細胞凋亡。因此本實驗證實月桂酸確實可有效誘導微型核醣核酸-378表現量提升於KRAS或BRAF基因突變型的大腸直腸癌細胞中，並抑制ERK1/2蛋白質表現，表皮生長因子受器抗體的療效也因此獲得極大的改善。由於月桂酸在日常飲食中即可從橄欖油中獲取，本研究的發現對於目前棘手的臨床基因突變型大腸直腸癌治療方向，將提供全新且有效的安全治療策略。

Colorectal cancer (CRC) is one of the most common human malignancies in Taiwan. Clinically, 40% of CRC patients with KRAS/BRAF mutation present resistance to the anti-EGFR antibody (Cetuximab, Erbitux) therapy. In our previous findings, we have identified increasing expression level of miR-378 in the KRAS or BRAF mutant CRC cells are associated with the cells sensitivity to the anti-EGFR antibody treatment. As known that miR-378 is encoded by PGC-1β gene, which also regulates the lipid metabolism. Therefore, we hypothesized that to increase Lauric acid (C12:0) in the cells might also enhance the expression of miR-378 in the cancer cells; further, it will stimulate the cells response to anti-EGFR antibody treatment. In current study, three of CRC cell lines contain with KRAS (HCT 116 & SW 480) and BRAF (HT 29) mutations were cultured with Lauric acid. The results showed once enhancing the expression level of miR-378, consequentially decreased cell survival by treating anti-EGFR antibody could be observed. Moreover, reduced ERK1/2 protein expression has been found after Lauric acid treated in CRC cells. All the results provided evidences of Lauric acid might significantly improve anti-EGFR antibody response to KRAS/BRAF mutate CRC cells. As known that Lauric acid is easy derived from olive oil, and our results suggest a novel, useful, and safe strategy for those CRC patients who contain with KRAS or BRAF.

中文摘要....................................................i
ABSTRACT..................................................ii
誌 謝....................................................iii
目 錄.....................................................iv
圖目錄.....................................................vi
表目錄....................................................vii
第一章 導論.................................................1
1.1大腸直腸癌...............................................1
1.1.1大腸直腸癌的嚴重性.......................................1
1.1.2遺傳性與偶發性大腸直腸癌基因上的差異........................2
1.1.3有絲分裂活化蛋白質激酶（MAPK）路徑於大腸直腸癌中之重要性.......3
1.1.4有絲分裂活化蛋白質激酶（MAPK）路徑突變對表皮生長因子受器抗體(anti- EGFR antibodies)的影響...............................6
1.2微型核醣核酸..............................................6
1.2.1微型核醣核酸簡介.........................................6
1.2.2微型核醣核酸與大腸直腸癌..................................7
1.2.3微型核醣核酸-378與大腸直腸癌中有絲分裂活化蛋白質激酶（MAPK）路徑的關係......................................................7
1.2.4微型核醣核酸-378與過氧化物酶體增殖物啟動受體γ輔啟動因子1β（PGC-1β）的關係..................................................8
第二章 研究動機與目標........................................12
2.1 研究動機...............................................12
2.2 研究目標...............................................12
第三章 材料與方法............................................14
3.1 細胞培養...............................................14
3.2 月桂酸培養基配置.........................................18
3.3 月桂酸之自由基脂肪酸定量..................................19
3.4 總核醣核酸(total RNA)萃取...............................20
3.5 細胞內核醣核酸(RNA)表現相對定量...........................21
3.6 細胞活性分析............................................26
3.7 酵素免疫分析............................................27
3.8 統計方法...............................................28
第四章 研究結果.............................................29
4.1 大腸直腸癌細胞株對月桂酸之消耗率............................29
4.2 月桂酸培養基培養大腸直腸癌細胞株之生長曲線...................30
4.3 微型核醣核酸-378表現提升於月桂酸培養基培養之大腸直腸癌細胞株....30
4.4 不同濃度月桂酸與大腸直腸癌細胞株生長速率的關係................31
4.5 月桂酸培養基培養後施以表皮生長因子受器抗體(anti-EGFR antibody)改善大腸直腸癌抗藥性...........................................34
4.6 月桂酸培養基降低大腸直腸癌細胞株細胞外訊號控制激酶(ERK1/2)表現 36
第五章 討論................................................38
5.1 大腸直腸癌細胞株的生長與月桂酸消耗..........................38
5.2 月桂酸誘導大腸直腸癌細胞株表現微型核糖核酸-378...............38
5.3大腸直腸癌經月桂酸培養基培養後對anti-EGFR抗體產生反應..........39
5.4 微型核醣核酸-378抑制細胞外訊號控制激酶(ERK)表現..............40
第六章 結論................................................42
參考文獻...................................................44
附錄......................................................51
主要耗材...................................................51
主要分析儀器................................................53

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