CGI-58缺失介导TAMs脂质沉积促进结肠癌恶性进展的效应及机制研究.

Inflammatory microenvironment mediated by activation of tumor-associated macrophages (TAMs) is causally linked to the tumor progression, while the mechanism of TAM activation is not well understood. Based on the observation of CGI-58 deficiency-correlated with lipid accumulation and macrophage activation, this study aimed to explore the mechanisms and effects of CGI-58-mediated FOXO1 activation by lipid accumulation, elucidate the roles of CGI-58/FOXO1 pathway in proliferation, apoptosis and invasion of colon cancer cells in co-culture system (macrophages-colon cancer cells) with CGI-58 knockout and FOXO1 intervention in macrophages, and reveal the roles of macrophage CGI-58 in the malignant progression of colon cancer by subcutaneous or caudal vein xenograft experiments in macrophage CGI-58 specific knockout mice. We are the first, according to the abnormality of lipid metabolism in TAMs, to claim the roles of CGI-58 in chronic inflammation and colon cancer, which will shed light on the prevention and therapy strategies of colon cancer via tumor microenvironment intervention.

肿瘤相关巨噬细胞（TAMs）活化介导的炎性微环境在肿瘤恶性进展过程中起重要作用，但TAMs活化的机制尚不清楚。本研究在发现结肠癌TAMs中CGI-58缺失与脂质沉积和巨噬细胞激活相关的基础上，拟在巨噬细胞-结肠癌细胞共培养体系中，敲低巨噬细胞CGI-58，联合FOXO1表达干预，解析巨噬细胞CGI-58介导的脂质沉积活化FOXO1的机制及效应；阐明巨噬细胞CGI-58/FOXO1通路对结肠癌细胞增殖、凋亡和侵袭能力的影响；并在巨噬细胞CGI-58基因特异性敲除的小鼠模型上，经皮下或尾静脉进行荷瘤实验，揭示巨噬细胞CGI-58缺失对结肠癌恶性进展的影响。本研究以TAMs脂质代谢异常为切入点，率先解析TAMs CGI-58在慢性炎症和结肠癌恶性进展的中的作用，研究结果对于从肿瘤微环境角度寻找结肠癌的有效防治策略有重要指导意义。

肿瘤相关巨噬细胞（TAMs）活化介导的炎性微环境在肿瘤恶性进展过程中起重要作用，但TAMs活化的机制尚不清楚。本研究在发现结肠癌TAMs中CGI-58表达异常与脂质沉积和巨噬细胞激活相关的基础上，在巨噬细胞-结肠癌细胞共培养体系中，敲低巨噬细胞CGI-58，联合FOXO1表达干预，解析巨噬细胞CGI-58介导的脂质沉积活化FOXO1的机制及效应；阐明巨噬细胞CGI-58对结肠癌细胞增殖、凋亡和侵袭能力的影响；并在巨噬细胞CGI-58条件转基因小鼠模型上，经皮下或尾静脉进行荷瘤实验，揭示巨噬细胞CGI-58对结肠癌恶性进展的影响。在本基金的资助下，我们创新性地发现：（1）巨噬细胞CGI-58缺失可活化ROS依赖的炎性小体信号通路，进而促进IL-1β等炎症因子分泌；（2）巨噬细胞CGI-58缺失也可以激活FOXO1转录活性，进而促进IL-1β的转录表达；（3）巨噬细胞CGI-58可抑制亚精胺合成途径，进而促进结肠癌恶性进展；其机制为：CGI-58可通过抑制ROS生成，进而抑制C/EBPε表达及活性，而亚精胺合成酶(SRM)被我们首次鉴定为C/EBPε的靶基因。CGI-58调控炎症因子分泌机制的阐明，为干预代谢性、慢性炎症性疾病，如肥胖、肿瘤等，提供了新的思路和潜在的靶点。巨噬细胞CGI-58调控结肠癌恶性进展机制的阐明，拓展了我们对巨噬细胞CGI-58功能的认识，首次提出了CGI-58对多胺代谢的调控作用，也为临床上从肿瘤微环境角度防治结肠癌提供了重要的干预通路和关键靶点。