脂肪酸受体GPR120介导的癌相关成纤维细胞重编程机制及其对乳腺癌进程影响研究

项目名称： 脂肪酸受体GPR120介导的癌相关成纤维细胞重编程机制及其对乳腺癌进程影响研究

项目编号： No.81502506

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 吴琼

作者单位： 苏州大学

项目金额： 18万元

中文摘要： 肿瘤微环境为恶性肿瘤生长和转移提供土壤，其中癌相关成纤维细胞（CAF）发挥重要作用，但相关重编程作用和调控机制尚不清楚。乳腺癌存在特殊脂肪酸代谢压力，游离脂肪酸（FFAs）作用于相应GPR120受体影响细胞多种生物学行为。我们预初实验发现，人乳腺癌肿瘤组织中4种长链FFAs异常升高，GPR120激活后正常人乳腺成纤维细胞（HMF）促进肿瘤生长，提示FFAs/GPR120信号与CAF重编程相关。鉴于趋化因子在CAF促肿瘤中的作用，我们发现GPR120激活后HMF的CCL2、CCL5分泌和表观调控因子EZH2表达上升，代谢相关调节因子PPAR-γ下降。本项目在前期工作基础上，拟聚焦乳腺癌微环境中脂肪酸代谢异常和CAF，设想研究FFAs/GPR120介导的CAF重编程及其通过促肿瘤炎症反应和转移影响乳腺癌恶性进程的作用，明确关键信号通路和调控靶点；藉此为建立靶向肿瘤微环境的肿瘤治疗新策略提供依据

中文关键词： C21_乳腺肿瘤；GPR120；癌相关成纤维细胞；重编程；肿瘤转移

英文摘要： Tumor microenvironment provides the soil for malignant tumor growth and metastasis, in which cancer-associated fibroblasts (CAF) play an important role. However, the function and regulation mechanism of CAF reprogramming remain unclear. It has been shown that special fatty acid metabolism pressure exists in breast cancer microenvironment. And free fatty acids (FFAs) corresponding to fatty acid receptor GPR120 will influence a variety of cell biology behaviors. Our preliminary experiment showed that four kinds of FFAs including DHA, fatty acid, linoleic acid and eicosapentaenoic acid abnormally elevated in human breast cancer tumor tissues. And normal human Mammary Fibroblast (HMF) can promote the growth of breast cancer once its GPR120 activated. These indicate that FFAs/GPR120 signal is associated with CAF reprogramming, while the exact mechanism still remains unknown. Given the significant role of chemokines in the tumor promoting process of CAF, we also found that activation of GPR120 results a notable evaluated level of chemokine CCL2, CCL5 and epigenetic regulating factor EZH2, but remarkablely decline of metabolic regulation factor PPAR-γ in HMF. Therefore, on the basis of previous work, we further take abnormal fatty acid metabolism and CAF in the breast cancer microenvironment as as the original focus, explore FFA/GPR120 signal induced CAF reprogramming and its effects on breast cancer progress by promoting of tumor inflammatory and metastasis, and clarify associated molecular signaling pathways and key control targets, whereby providing experimental evidence for establishing new tumor therapeutic strategies targeting tumor microenvironment.

英文关键词： breast cancer;GPR120;cancer-associated fibroblast;reprogramming;tumor metastasis