巨噬细胞中FABP4通过结合ATPB诱导PGC-1α入核调控CCL1表达进而促进神经母细胞瘤转移的机制研究

肿瘤相关巨噬细胞（TAM）在神经母细胞瘤（NB）转移过程中起重要作用，但机制未明。我们前期对NB患儿样本进行转录组分析发现转移组中FABP4表达显著上调，且特异表达于巨噬细胞；过表达FABP4可增加TAM中CCL1的分泌，促进NB细胞迁移。FABP4为什么会促进TAM中CCL1分泌?预实验发现FABP4可特异性结合ATPB，过表达FABP4可促进ATP生成及PGC-1α入核；软件预测PGC-1α可与CCL1启动子发生结合。我们推测：TAM中FABP4可能通过结合ATPB促进ATP生成，诱导PGC-1α入核并调控CCL1表达，进而促进NB细胞转移。为此本项目拟：1）探索TAM 中FABP4与ATPB相互作用对PGC-1α的影响，同时验证PGC-1α对CCL1的转录调控作用；2）分别通过体内NB原位和转移模型验证TAM中FABP4促转移作用。本研究将为NB的免疫治疗提供新的理论研究策略。

Tumor-associated macrophages play key roles in tumor growth and metastasis, but their function and mechanism in neuroblastoma(NB) has not been fully studied. In our previous study, RNA-sequence of NB samples(non-metastatic group vs metastatic group) was performed, we identified FABP4, which was specifically expressed in macrophages, has positive correlationship with NB progression. In vitro, conditional mediums derived from macrophages with FABP4 overpression significantly promotes the migration of NB cells, which inhibited by FABP4 knockdown. FABP4 also increased the phenotype of MRC1+ TIE2+ macrophages and subsequent CCL1 secretion; Mechantically, FABP4 could accelerate PGC-1α phosphorylation through binding with ATPB; Moreover, ‘TF targets’ website revealed PGC-1α could binding with the promoter region of CCL1. Therefore, we hypothesis that FABP4 in macrophages accelerated MRC1+ TIE2+ phenotype and PGC-1α phosphorylation through binding with ATPB, thereby raising CCL1 secretion and metastasis of NB cells. Further studies were needed to clarify the regulation of FABP4 and ATPB interaction, as well as their effects on PGC-1 α and CCL1 expression; Besides, In vitro, cell line-based xenograft orthotopic NB model, as well as metastasic model were also applied to explore mechanism involving downstream signaling pathway of FABP4 in macrophages and their roles in NB. This study will provide proof-of-concept evidence for the value of macrophage targeting in NB immunotherapy and unveil a different perspective for the exploitation of FABP4 in the treatment of NB.