miR-671-5p/FGFR2/uPA通路在食管鳞癌肿瘤相关成纤维细胞中的作用机制研究

项目名称： miR-671-5p/FGFR2/uPA通路在食管鳞癌肿瘤相关成纤维细胞中的作用机制研究

项目编号： No.81472337

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 洪岸

作者单位： 暨南大学

项目金额： 72万元

中文摘要： FGFR2与肿瘤的发生发展重要相关。它被发现是食管鳞癌肿瘤相关成纤维细胞（CAF）的标志蛋白，但相关分子调控机制却没有进一步报道。我们前期研究已发现FGFR2的3'UTR是miR-167-5p的靶向序列，且CAF比癌旁的正常成纤维细胞更多地分泌ActivinA、IFN-γ和uPA等，并发现过表达FGFRR2的293细胞模型中uPA的表达水平显著上调，提示uPA可能位于FGFR2的下游。本研究将分析FGFR2的3'UTR中特定序列的活性，并在细胞中过表达和干扰miR-167-5p，明确二者的调控关系；检测并抑制uPA及FGFR2相关通路，分析关键节点蛋白的作用，探讨二者的调控机制；并深入研究FGFR2是如何经由miRNA分子和蛋白因子促进了食管鳞癌的恶化，分析其分子作用机制。本课题的新发现将进一步解析FGFR2与食管鳞癌发生的关系，获得FGFR2分子调控和作用的新知识，补充肿瘤发生机制。

中文关键词： 成纤维细胞生长因子受体2；C06_食管肿瘤；肿瘤相关成纤维细胞；微小RNA

英文摘要： FGFR2 plays an essential role in growth and development. High expression level of FGFR2 was found in some tumors, indicating that FGFR2 was associated with tumor development and progression. High expression level of FGFR2 was found in cancer-associated fibroblasts (CAFs), but not in tumor-surrounding stromal tissues of Esophageal carcinoma (ESCC), making it a CAF-specific marker. But there is no detailed knowledge about why and how FGFR2 is overespressed. In our previous study, we found that miR-671-5p directly bound to 3'UTR of FGFR2, leading to FGFR2 mRNA degradation. Antibody array indicated that expression levels of some secreted proteins, including Activin A, IFN-gamma and uPA, were significantly higher in the supernantant of FGFR2-positive CAFs than in NFs (normal fibroblasts). uPA was shown higher expression level in stably FGFR2-expressing cells (293A-FGFR2) than in empty vector transfected cells (293A), suggesting uPA might be an downstream protein of FGFR2. In the study, we committed to confirm the relationship between FGFR2 and miR-671-5p, through analyzing activity of 3'-UTR of FGFR2, and influence of miR-671-5p on ESCC cells; confirm the correlation of FGFR2 and uPA, by detecting expression and phosphorylation of key proteins in FGFR2 and uPA signaling networks. Thus, how miR-671-5p-FGFR2-uPA axis provides a suitable microenvironment for tumor development and progression in ESCC. Based on our study, we will provide further knowledge on functions of FGFR2 and relationship between FGFR2 and ESCC progression, supporting for future development of anticancer drugs.

英文关键词： FGFR2;Esophageal squamous cell carcinoma;cancer associate fibroblast;miRNA