脂肪細胞誘導三陰性乳癌惡性發展之機制探討

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題名:	脂肪細胞誘導三陰性乳癌惡性發展之機制探討 Investigating the mechanisms of malignant progression in adipocyte-fueled triple-negative breast cancer
作者:	王嬿茹 WANG, YEN-JU
貢獻者:	醫學科學研究所碩士班林政緯
關鍵詞:	肥胖;脂肪酸氧化;氧化磷酸化;轉錄因子YAP;乳癌 obesity;fatty acid oxidation;OXPHOS;YAP;breast cancer
日期:	2021-07-13
上傳時間:	2022-03-16 23:01:01 (UTC+8)
摘要:	肥胖是許多癌症的危險因子，包括乳癌在內，其與高風險和不良的預後有關。肥胖會導致有利於腫瘤發展的微環境，而肥胖引起的發炎反應為促進癌症進展的主要因素。雖然激素紊亂被認為是乳腺腫瘤生長的危險因素，但是，肥胖與缺乏賀爾蒙受體的三陰性乳癌，對於女性預後不良也有密切相關。因此，探討肥胖誘導三陰性乳癌惡性發展之調控機制更顯重要性。在本篇研究中，我們發現飲食誘導的肥胖導致了小鼠三陰性乳癌具有較高的生長及侵犯能力。我們驗證了飲食誘導的肥胖影響了乳癌細胞傾向脂肪酸氧化的代謝重整，並且活化了Hippo pathway的重要調控因子yes-associated protein（YAP）。我們進一步分析，發現YAP能夠調控抗氧化相關基因轉錄以影響粒線體的氧化還原平衡，這使得腫瘤細胞能夠減少由脂肪酸氧化及氧化磷酸化所引起的氧化壓力，進而促進腫瘤的進展。此外，我們還證實了脂肪細胞調控了小鼠和人類三陰性乳癌細胞的脂肪酸氧化及活化YAP，進而調控抗氧化能力，進而影響乳腺腫瘤發展。且在臨床數據中，肥胖相關基因表達較高的乳癌患者具有較高YAP相關基因及抗氧化基因表現。本篇的研究結果證實，脂肪細胞促進的代謝重整及YAP能調節粒線體氧化還原平衡與抗氧化能都和乳癌發展有著密不可分的關係。 Obesity is a risk factor for many cancers, including breast cancer, and is correlated with both high risk and poor prognosis. Obesity leads to a tumor conducive microenvironment, and obesity-induced inflammation is a major factor in promoting cancer progression. Although disorder of hormone is considered as a risk factor for breast tumor growth, obesity is associated with poor outcomes among women diagnosed with triple-negative breast cancer (TNBC), which is a hormone-independent subtype. Therefore, the underlying mechanisms of obesity-induced changes of tumor microenvironment in TNBC cells are far more complicated and needs to be elucidated. In the present study, we identified that diet-induced obesity (DIO) promoted initiation, growth and metastasis of murine TNBC cells. We found that DIO promoted a metabolic switch to fatty acid oxidation (FAO) and accompanied by coordinated activation of the yes-associated protein (YAP) signaling. Specifically, YAP governs mitochondrial redox homeostasis via transcriptionally regulation of the antioxidant-related genes expression, which renders tumor cells to be capable of extenuating FAO-elicited oxidative stress and thereby facilitating tumor progression. Moreover, adipocytes were identified to be responsible for enhancing the FAO-YAP axis and anti-oxidative capacity in both murine and human TNBC cells, and breast cancer patients with higher expression of obesity-associated genes were positively correlated to the YAP signaling. Our findings identify that YAP plays a key role in regulating mitochondrial redox homeostasis for obesity-mediated metabolic adaptation and breast tumor progression.
描述:	碩士指導教授：林政緯委員：何元順委員：李崑豪
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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