肥胖基因PID1调控肝癌MDSCs脂质代谢和功能重塑的机制研究

肝癌微环境脂质代谢产物可促进髓源性抑制细胞（MDSCs）迁移和活化，细胞内脂肪酸氧化可增强其活性。我们前期研究发现肥胖基因PID1（磷酸酪氨酸互作结构域1）肝脏高表达呈现癌基因样作用，伴微环境酸性代谢产物增加及MDSCs聚集。胞内PID1高表达引起脂肪酸转运分子LRP1，脂肪酸结合、合成相关分子FABP4和SREBP1等上调，MDSCs免疫抑制活性增强。PID1是否参与肝癌免疫调控，如何发挥作用未见报道。我们拟于临床肝癌样本、基因修饰小鼠及MDSCs清除和细胞过继转移小鼠模型等，通过肝癌细胞及微环境脂质代谢产物分析，MDSCs中脂质转运、代谢和细胞增殖调节轴及细胞免疫功能分析，研究PID1通过肝癌微环境调控MDSCs募集活化，以及直接调控胞内脂肪酸代谢重塑MDSCs功能的作用。最终揭示PID1介导MDSCs内外脂肪酸感应和代谢、增殖信号转导和活性的脂质代谢调控肿瘤免疫新机制。

Lipid metabolites in hepatocellular carcinoma(HCC) microenvironment accelerate myeloid derived suppressor cells(MDSCs) migration and activation, and fatty acid oxidation intracellularly promotes their effect. In our previous studies, we found that obesity gene PID1(Phosphotyrosine interaction domain containing 1) played an oncogene role in promoting hepatocarcinogenesis with the high expression of PID1 in liver, and it was accompanied with increased metabolites like fatty acids in tumor microenvironment, and MDSCs accumulated around the liver; While, increased expression of PID1 in MDSCs activated expression of fatty acid transport molecules, and higher expression of lipid binding and synthesis related molecules like FABP4 and SREBP1 in MDSCs, and strengthened immunosuppression of MDSCs to tumor. Whether PID1 is the key molecule regulating anti-cancer immunity, and how it works is unknown yet. .Therefore, we will adopt HCC tissues, transgene model, MDSCs removal and adoptive transfer of modified MDSCs in animal model of liver cancer, and investigate metabolites in HCC microenvironment, molecule axis of lipid regulatory and cell proliferation, and cell function of MDSCs upon PID1 action. .We will demonstrate that PID1 modulates MDSCs migration in cancer microenvironment; and regulates function of MDSCs by fatty acid metabolism intracellularly. Our goal is to find the novel mechanism for association of lipid metabolism and immunity by PID1 in liver cancer involved intra- or extra- fatty acid sensing, metabolism, signal transduction and activity.