根據世界衛生組織2018 年的報告，結直腸癌是全世界癌症死亡的第二大原因。目前最常用的治療方法為手術切除、化療及放療。近期多種化療藥物研究顯示，癌症患者在單獨給予或併用化療藥物能顯著改善其總體存活率。奧沙利鉑和5-FU 常用於治療結腸癌; 然而，奧沙利鉑的臨床應用受到腎毒性和耐藥性的限制。此外，化療藥物耐藥性仍是癌症醫學上尚未闡明的重要課題，而其化療藥抗性的機制迄今也還未明瞭。在過去十年間的研究指出，微小RNA 表現量的改變與癌症進展相關，並提出許多關miRNA 在耐藥性發展中起作用的機制。作為參與miRNA 生合成的關鍵酶，Drosha 的下調與許多癌症的預後不良有關。因此，在我們先前的研究中，我們使用HCT116 和奧沙利鉑抗性HCT116 細胞株來進一步探討鉑類藥物作用和耐藥機制。根據我們先前的研究顯示，Drosha 的下調增加了人類結腸癌細胞株HCT116 中對奧沙利鉑的抗性。為了進一步研究miRNA 在化療藥抗性機制中的作用，我們希望找到一種潛在的miRNA，它受到Drosha 下調的影響，進而在結腸癌中發揮化療耐藥作用。我們首先通過次世代測序（NGS）分析miRNA 整體的表現量變化。然後利用生物資訊學分析工具篩選出具潛力的候選miRNA。並接著確認候選miRNA 的表達量，通過qRT-PCR 證實了HCT116 奧沙利鉑抗性細胞株和HCT116 shDROSHA 細胞中miR-33a-5p，miR-1229-3p 和miR-4738-3p 的增加。為了研究miRNA 對人類結腸癌的化學抗性作用，我們使用具有高度專一性的antagomir 轉染HCT116 奧沙利鉑抗性細胞以減少候選miRNA 表現量。接著利用qRT-PCR 以驗證我們的生物資訊學預測。Antagomir-33a-5p 的miRNA 減弱效果得到了證實，我們的初步功能性探討結果表明，減弱miR-33a-5p 可以略微增強細胞遷移和細胞增殖能力。 然而，mir-33a-5p 在奧沙利鉑耐藥性結直腸癌中的特徵尚不完全清楚，未來還需要更多的實驗以供進一步研究。本論文提出的研究可能有助於改進miRNA 導向的治療方法，並可能為antagomirs 在癌症醫學中的應用上提供新的契機。

According to the world health organization, 2018, colorectal cancer is the second leading cause of cancer mortality all over the world. Nowadays, the most commonly used treatment, such as surgical resection, chemotherapy, and radiotherapy. Advancement of different chemotherapy regimens have improved patients overall survival. Oxaliplatin and 5-FU are widely used in treating colon cancer; however, the clinical use of oxaliplatin is limited by nephrotoxicity and drug resistance. Moreover, chemotherapeutic drug resistance is still a significant barrier in effective management of resistant tumor. The mechanisms of chemo-resistance are yet to be fully clarified. Over the past decade, altered Micro RNAs levels are associated with cancer progression. Many mechanisms have been postulated for the roles that miRNAs play in the development of drug resistance. As a key enzyme involved in miRNA biogenesis, downregulation of Drosha is associated with poor prognosis in many cancers. Therefore, in our previous study, we used HCT116 and oxaliplatin resistant HCT116 cell lines to characterize platinum drug action and further explore the mechanism of drug resistance. Our last data showed that downregulation of Drosha increases the resistance to oxaliplatin in human colon cancer cell line HCT116. To further investigate the role of miRNA in the chemo-resistant mechanism, we aim to find a potential miRNA, which is influenced by downregulation of Drosha and consequently play a chemotherapy-resistance role in colon cancer. We first analyze the global alter of miRNA expression by next-generation sequencing (NGS). And then make use of bioinformatics analysis tool to filter the potential candidate miRNA. We next examined the expression of candidate miRNA, qRT-PCR confirmed an increase of miR-33a-5p, miR-1229-3p, and miR-4738-3p in both HCT116 oxaliplatin resistant cell line and HCT116 shDROSHA cell. To investigate the effects of miRNAs on chemo-resistance CRC cell, the HCT116 oxaliplatin resistance cell was transfected with specific antagomirs to knockdown candidate miRNAs. Then qRT-PCR was performed to validate our bioinformatics prediction. We confirmed the knockdown effect of antagomir-33a-5p, and our preliminary functional assay result suggests that knockdown miR-33a-5p slightly improve cell migration and cell proliferation. However, the characteristics of mir-33a-5p in oxaliplatin-resistant colorectal cancer are not completely clear, and more experiments are needed in the future for further investigation. The research presented in this thesis may aid in the rational design of improved miRNAs based therapy and yield insights into the use of antagomirs for the cancer therapy application.

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