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| 題名: | 新型核醣核酸還原?M2抑制劑COH29誘導大腸癌細胞死亡之分子機制探討
Elucidation of the molecular mechanism of a novel ribonucleotide reductase M2 inhibitor COH29-induced cell death in colon cancer cells |
| 作者: | 葉雲萱
YEH, YUN-HSUAN |
| 貢獻者: | 癌症生物學與藥物研發研究所碩士班
黃翠琴 |
| 關鍵詞: | 大腸直腸癌;COH29;RNR抑制劑
Colorectal Cancer;COH29;RNR inhibitor |
| 日期: | 2023-07-13 |
| 上傳時間: | 2023-12-07 10:01:39 (UTC+8) |
| 摘要: | 癌症是導致國人死亡的主要原因之一，而大腸直腸癌（CRC）更是2020年全球死亡的三大原因之一。根據我國衛生福利部國民健康署調查顯示，大腸直腸癌發生與死亡率每年皆呈現快速增加的趨勢，位居所有癌症的發生率及死亡率的第二或第三名。儘管目前國內對於大腸直腸癌的藥物研發及研究持續地進行，但高死亡率仍為目前最大的挑戰。核糖核?酸還原?（RNR）由核糖核?酸還原? M2（RRM2）與核糖核?酸還原? M1（RRM1）所構成，是催化核糖核?二磷酸（NDP）形成2'-脫氧核糖核?二磷酸（dNDP）的酵素。之前的研究顯示， RRM2 在 DNA 合成、細胞生長、轉移以及腫瘤細胞的耐藥性扮演關鍵性的作用，並可能是一個理想的大腸癌的檢測和預後不良的指標。先前開發的 RNR 抑制劑 COH29 會透過抑制 RRM1 和 RRM2 的結合進而抑制 RNR 的活性，且已有文獻顯示其具有抗癌效果，但其詳細作用機制目前尚未未釐清。因此本研究主要目標：利用系統生物學方法全面性瞭解及探討 COH29 在大腸直腸癌中的抗癌效果及分子機轉。初步研究結果證實 COH29 能夠有效抑制癌細胞的存活及聚落形成的能力，並且影響癌細胞粒線體的膜電位達到抑制癌細胞生存。經由轉錄體學的分析結果發現 COH29 會影響 p53 參與的調控路徑，以及活化細胞凋亡的基因表現，結果將深入了解 COH29 抑癌的作用機制，有助於發展新的大腸直腸癌治療方法。
Cancer is one of the leading causes of death in the country, and colorectal cancer (CRC) is among the top three causes of global mortality in 2020. According to the survey conducted by the Health Promotion Administration, Ministry of Health and Welfare in our country, the incidence and mortality rates of colorectal cancer have been rapidly increasing, ranking second or third in terms of cancer incidence and mortality rates. Despite ongoing research and development of drugs for colorectal cancer domestically, the high mortality rate remains the biggest challenge.Ribonucleotide reductase (RNR) consists of two subunits, ribonucleotide reductase M2 (RRM2) and ribonucleotide reductase M1 (RRM1), and is responsible for catalyzing the formation of 2'-deoxyribonucleotides (dNDPs) from ribonucleoside diphosphates (NDPs). Previous studies have shown that RRM2 plays a crucial role in DNA synthesis, cell growth, metastasis, and drug resistance in tumor cells, making it a potential marker for colorectal cancer detection and poor prognosis.The previously developed RNR inhibitor, COH29, inhibits the activity of RNR by disrupting the binding of RRM1 and RRM2. Existing literature has shown its anticancer effects, but the detailed mechanism of action is still unclear. Therefore, the main objective of this study is to comprehensively understand and investigate the anticancer effects and molecular mechanisms of COH29 in colorectal cancer using systems biology approaches. Preliminary research results have confirmed that COH29 effectively inhibits cancer cell survival and colony formation ability, and it affects the mitochondrial membrane potential of cancer cells, leading to their suppression. Transcriptomic analysis reveals that COH29 affects the p53 -regulated pathway and gene expression involved in activating cell apoptosis. These results will provide deeper insights into the anticancer mechanisms of COH29 and contribute to the development of new treatment methods for colorectal cancer. |
| 描述: | 碩士
指導教授:黃翠琴
委員:黃翠琴
委員:夏詩閔
委員:張心儀 |
| 資料類型: | thesis |
| 顯示於類別: | [癌症生物學與藥物研發研究所] 博碩士論文
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