E3泛素连接酶Cullin3通过IL-4R-STAT6信号通路调节肿瘤相关巨噬细胞的功能及在肿瘤生长与转移中的作用研究

Tumor associated macrophages play an important role in tumor growth and metastasis. Cullin3 has diverse roles in regulating multiple cellular physiological process. However, the role of Cullin3 in regulating tumor associated macrophages remains to be elucidated. Our preliminary data indicated that macrophage-specific Cullin3-knockout mice are prone to promote tumor growth and metastasis when compared with WT mice, accompanied by more pro-tumoral tumor associated macrophages infiltration in tumor and metastases. We found that Cullin3 interacts with IL-4R and orchestrates STAT6 signaling pathway in macrophages. Based on previous findings, we hypothesized that Cullin3 may control tumorigenesis and metastasis through regulating IL-4R-STAT6 signaling pathway in tumor associated macrophages. The present project intends to a further study by using animal model in vivo, cellular model in vitro, aiming to illustrate the effect of Cullin3 in the process of tumorigenesis and metastasis through regulating tumor associated macrophages.

肿瘤相关巨噬细胞（TAM）与肿瘤的生长与转移密切相关，解析其调控机制对肿瘤的诊疗具有重要意义。E3泛素连接酶Cullin3调节细胞内各种生理过程，但其在肿瘤相关巨噬细胞及其介导的肿瘤生长与转移中的功能却不清楚。申请人前期研究表明：巨噬细胞特异性缺失Cullin3的小鼠有更强的肿瘤生长与转移能力，而缺失Cullin3的肿瘤相关巨噬细胞展现出促肿瘤特性，进一步发现Cullin3能够结合IL-4R并能调节STAT6信号通路。基于此，我们提出假说：Cullin3通过与IL-4R结合影响STAT6信号通路从而调节肿瘤相关巨噬细胞功能及肿瘤生长与转移。本项目拟进一步利用小鼠肿瘤模型阐明Cullin3调节肿瘤相关巨噬细胞在肿瘤生长与转移中的作用，通过肿瘤相关巨噬细胞功能实验检测Cullin3对其调节作用，还将阐明Cullin3与IL-4R相互作用调节STAT6信号通路与肿瘤相关巨噬细胞功能的分子机制。

肿瘤相关巨噬细胞与肿瘤的生长与转移密切相关，解析其调控机制对肿瘤的诊疗具有重要意义。E3泛素连接酶Cullin3调节细胞内各种生理过程，但其在肿瘤相关巨噬细胞及其介导的肿瘤生长与转移中的功能却不清楚。本项目通过构建多种昂体内外肿瘤生长与转移模型，从而表明：巨噬细胞特异性缺失Cullin3的小鼠有更强的肿瘤生长与转移能力，而缺失Cullin3的肿瘤相关巨噬细胞展现出促肿瘤特性。通过体内外巨噬细胞功能实验，本项目发现Cullin3能够调节巨噬细胞杀伤与吞噬能力，在肿瘤组织中，缺失Cullin3的巨噬细胞肿瘤杀伤能力也减弱。通过筛选，本项目找到Cullin3的接头蛋白Rhobtb3能够结合IL-4R并能调节IL-4R的内吞与信号通路的激活。以上研究成果不仅首次解释巨噬细胞Cullin3在肿瘤生长与转移中的作用，还厘清Cullin3调节巨噬细胞的分子机制。