- 學位論文
利用月桂酸誘導微型核醣核酸-378表現以改善表皮生長因子受器抗體對KRAS/BRAF突變大腸直腸癌之抗藥性
Up-regulation of miRNA-378 Induced by Lauric Acid Affecting anti-EGFR Antibody Sensitivity in KRAS/BRAF Mutation of Colorectal Cancer
摘要
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。
並列摘要
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.