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    題名: NRF2在胰臟癌腫瘤微環境所扮演角色之研究
    The Role of NRF2 in the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma
    作者: 盧昱維
    LU, YU-WEI
    貢獻者: 代謝與肥胖科學研究所碩士班
    黃士懿
    關鍵詞: 核轉錄相關因子NRF2;胰臟癌;癌症相關成纖維細胞
    NRF2;pancreatic cancer;cancer associate fibroblast
    日期: 2024-06-25
    上傳時間: 2024-10-14 13:50:00 (UTC+8)
    摘要: 由癌症相關成纖維細胞(cancer associate fibroblast, CAF)及腫瘤細胞相互作用所塑造的腫瘤微環境(tumor microenvironment, TME)，是造成胰臟癌預後極低的主要原因。其中，核轉錄相關因子NRF2 (nuclear factor erythroid 2-related factor 2)可結合抗氧化反應元件ARE (antioxidant response element, ARE)啟動下游抗氧化基因SLC7A11的表現，具有提升癌細胞抗氧化能力的效果，但NRF2於腫瘤周邊組織中表現是否會對CAF的有何影響還尚未清楚。因此，本篇研究將小鼠胰腺癌細胞Panc02細胞皮下注射在nrf2基因剔除及SLC7A11突變小鼠，探討NRF2對於周邊組織及癌細胞的影響為何?實驗結果發現，相較於SLC7A11突變小鼠，nrf2基因剔除的小鼠腫瘤體積較大，同時也觀察到，在腫瘤周邊組織中消除nrf2可能使腫瘤細胞有較快的生長。接著，我們進一步探討NRF2是否對於CAF形成有所影響，並研究NRF2對於成纖維細胞中glutamate及proline之代謝。最後，我們建立了3D立體培養模型，模擬腫瘤在體內生長情形，以了解NRF2於周邊組織中對於癌細胞的生長及球體形成的影響。綜合以上論述，本研究探討了NRF2在腫瘤周邊組織所扮演的角色，是否會對CAF的形成有所影響以及其代謝路徑，並且是否對腫瘤微環境的調控有潛在的機制。
    The tumor microenvironment is made up of interaction with tumor cells and cancer-associated fibroblasts (CAF); this is the primary reason for the extremely poor prognosis of pancreatic cancer. Among, Nuclear factor erythroid 2-related factor 2 (NRF2) can activate the downstream antioxidant gene SLC7A11 expression by binding to antioxidant response element (ARE), which enhances the oxidative stress resistance of cancer cells, but whether the expression of NRF2 in tumor periphery tissue has an impact on the formation of CAF, it is unclear. In this study, we use mice pancreatic cancer cell Panc02 to subcutaneously inject into mice with NRF2 gene knockout (KO) and SLC7A11 mutation in order to investigate the impact of NRF2 on the peripheral tissue and cancer cells. The experimental results revealed that mice with SLC7A11 mutations had larger tumor volumes than mice with NRF2 KO. We observed that the elimination of NRF2 in the tumor microenvironment may lead to faster growth of tumor cells in the surrounding tissue. Next, we explore whether NRF2 impacts the formation of CAF and study the effects of NRF2 on glutamate and proline metabolism in fibroblasts. Finally, we establish a 3D co-culture model, using pancreatic cancer cell MiaPaCa-2 co-culture with normal cell HPNE-hTERT to simulate tumor growth in vivo, aiming to understand the impact of NRF2 on the growth of cancer cells and sphere formation in the surrounding tissue. Overall, this study aims to investigate the role of NRF2 in the tumor microenvironment, whether it impacts the formation of CAF, and whether there are potential mechanisms for its regulation of the tumor microenvironment.
    描述: 碩士
    指導教授：黃士懿
    口試委員：張?文
    口試委員：郭呈欽
    口試委員：黃士懿
    附註: 論文公開日期：2024-07-18
    資料類型: thesis
    顯示於類別:[代謝與肥胖科學研究所] 博碩士論文

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