孕激素耐药子宫内膜癌细胞分泌白介素6促进巨噬细胞向CXCL8表型分化的机制研究

Tumor-associated macrophages(TAMs) are essential key cells of immune regulation in endometrial cancer. In our previous work, we observed that M2 macrophages obviously infiltrated into endometrial cancer lesion and could secrete CXCL8 to suppress ERα expression, thus enhance the cancer progression. However, the origin and differentiation of these CXCL8+ macrophages are still unclear. Recently, we found the number of CXCL8+ macrophage is positively associated with IL-6 expression in progestin resistant endometrial cancer. Proteomics analysis showed IL-6 could influence the transcription of CXCL8 through β-catenin/c-Jun, and phosphorylated β-catenin can be modulated by SHP2. Hence, we make the hypothesis that progestin resistant endometrial cancer cells could secrete IL-6 to increase β-catenin phosphorylation through SHP2, and induce TAMs to CXCL8 phenotype. Therefore, CXCL8 positive TAMs could produce more CXCL8 to promote the cancer progression. This project aims to investigate the mechanisms of TAM polarization, and also to optimize the microenvironment of progestin resistant endometrial cancer.

子宫内膜癌（EC）中的肿瘤相关巨噬细胞（TAM）是调节肿瘤局部炎性环境的关键细胞。我们前期证实子宫内膜癌中大量浸润的M2型TAM能够分泌CXCL8（即IL-8）促进肿瘤进展。然而，这些CXCL8+TAM的来源和分化途径尚不清楚。我们近期发现孕激素耐药的子宫内膜癌中IL-6表达显著升高并伴有CXCL8+TAM浸润增多,蛋白质组学分析表明IL-6极有可能通过β-catenin/ c-Jun信号通路对TAM中的CXCL8转录产生影响，其中β-catenin的活性可能受蛋白酪氨酸磷酸酶（SHP2）调节。由此我们提出本课题假说：孕激素耐药子宫内膜癌细胞分泌的IL-6可能通过SHP2调节β-catenin磷酸化水平，从而诱导TAM向CXCL8表型分化并分泌CXCL8促进肿瘤进展。本课题旨在证实上述假说，明确TAM向CXCL8表型分化的具体机制，为改变子宫内膜癌孕激素耐药困局提供理论和实践依据。

子宫内膜癌（EC）中的肿瘤相关巨噬细胞（TAM）是调节肿瘤局部炎性环境的关键细胞。本课题以蛋白质组学和生物信息学分析孕激素耐药和非耐药子宫内膜癌细胞株分泌蛋白谱的差异为基础，旨在明确IL-6通过β-catenin/c-Jun调控TAM向CXCL8表型分化的具体分子机制。课题组已基本完成项目的预期目标，揭示了孕激素受体PR及雌激素受体ER在子宫内膜癌肿瘤微环境中免疫细胞谱系里的表达情况。进一步，课题组还发现了IL9在子宫内膜癌发生发展中的作用，特别是相关免疫细胞的作用。希望通过干预这一过程改变孕激素耐药的困局，为子宫内膜癌治疗提供新的理论和实践依据。