癌症病人在進行化學療法(chemotherapy)時，癌細胞常會產生抗藥性，導致化療失敗。根據過去文獻報導，Aurora-A與在抗藥性中扮演了非常重要的角色；Dicer和抗藥性也有相關性，可是目前角色還未被釐清。本論文主要想要探討Aurora-A和Dicer在大腸直腸癌細胞中，對於化療藥物5-FU和oxaliplatin的抗藥性所扮演的角色，並了解其作用機轉。我們發現，在大腸直腸癌細胞株中，處理oxaliplatin或5-FU會使得Dicer蛋白表現量下降，但不影響其mRNA的表現，而此現象是由於ubiquitination所導致的。另外，我們也發現在oxaliplatin處理之下，會去影響let-7a, miR-106b, miR-25的表現量。同時我們也發現，在oxaliplatin或5-FU的處理之下，Aurora-A不論是蛋白或mRNA表現量都有下降的情形產生，且Aurora-A的3’UTR活性也有下降的情形 。為了進一步研究大腸直腸癌抗藥性的機轉，我們建立了抗藥性細胞株，並且發現在抗藥性細胞株中Dicer以及Aurora-A蛋白的表現量皆多於母細胞株。增加Aurora-A會導致Dicer的蛋白表現量上升，以及細胞對於藥物的敏感性；反之亦然。我們的結果顯示，Aurora-A和Dicer蛋白表現量與大腸直腸癌細胞抗藥性的衍生有關，更詳細機制還需要更多的研究去釐清。

Chemotherapy has a good success rate in colorectal cancer; however, recurrence of colorectal cancer is still frequent due to the development of drug resistance. Aurora-A, a cell cycle-regulated kinase plays a role in colorectal cancer development and drug resistance. Dicer, one of the key enzymes of the miRNA biogenesis pathway, may involve in the chemoresistance through regulating the expression of microRNAs. However, the role of Dicer in chemoresistance remains unclear. In this study, we want to investigate the effect and molecular mechanism of Dicer and Aurora-A in chemoresistance. Our results showed that the protein level, but not the mRNA expression, of Dicer was decreased upon 5-FU or oxaliplatin treatment; whereas, both the expression levels of Aurora-A protein and mRNA were decreased when cells treated with 5-FU and oxaliplatin. Interestingly, luciferase activity of Aurora-A 3’UTR was decreased upon 5-FU and oxaliplatin treatment. To further investigate the mechanism, the chemoresistant cell lines were generated. The expression levels of Dicer and Aurora-A were increased in oxaliplatin resistant cell lines. Overexpressed Aurora-A could increase the expression of Dicer and potentiate the drug resistance in colorectal cancer cells; in contrast, knock-down expression of Aurora-A decreased Dicer protein expression and led to an enhanced drug sensitivity.

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