过氧化物酶体增殖体激活受体δ（PPARδ）在许多器官中促进炎症和致癌，但其潜在机制尚不清楚。在胃中，PPARδ显著增加了化学诱导因子Ccl20在胃上皮细胞中的表达，同时诱导了胃腺癌（GAC）。CCR6是CCL20的唯一受体。在这里，我们检查了PPARδ介导的Ccl20/Ccr6信号在GAC致癌中的作用，并研究了其潜在机制。使用PPARδ特异性拮抗剂GSK3787检查GSK3787对PpardTG小鼠中GAC的影响。使用RNAscope Duplex Assays测量胃和脾中的Ccl20和Ccr6水平。使用流式细胞术或免疫染色测量PpardTG小鼠中胃内浸润免疫细胞的亚组。通过酶联免疫吸附法定量测定小鼠血清中13种经过优化的促炎趋化因子。GSK3787显著抑制了PpardTG小鼠中GAC的致癌发展。PPARδ增加了Ccl20水平，以趋化Ccr6+免疫抑制细胞，包括肿瘤相关巨噬细胞、骨髓衍生抑制细胞和T调节细胞，但在胃组织中降低了CD8+ T细胞。GSK3787通过抑制Ccl20/Ccr6轴抑制了PPARδ诱导的胃免疫抑制作用。此外，在PpardTG小鼠发展胃肿瘤之前的年龄阶段，Ccl20蛋白水平在血清中增加，随着小鼠年龄的增长，Ccl20水平进一步增加。GSK3787降低了小鼠血清中PPARδ上调的Ccl20水平。PPARδ对Ccl20/Ccr6轴的失调通过重建胃肿瘤微环境促进了GAC的致癌发展。CCL20可能是GAC早期检测和进展的潜在生物标志物。© 2023. 作者。

Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In stomachs, PPARδ significantly increases chemokine Ccl20 expression in gastric epithelial cells while inducing gastric adenocarcinoma (GAC). CCR6 is the sole receptor of CCL20. Here, we examine the role of PPARδ-mediated Ccl20/Ccr6 signaling in GAC carcinogenesis and investigate the underlying mechanisms.The effects of PPARδ inhibition by its specific antagonist GSK3787 on GAC were examined in the mice with villin-promoter-driven PPARδ overexpression (PpardTG). RNAscope Duplex Assays were used to measure Ccl20 and Ccr6 levels in stomachs and spleens. Subsets of stomach-infiltrating immune cells were measured via flow cytometry or immunostaining in PpardTG mice fed GSK3787 or control diet. A panel of 13 optimized proinflammatory chemokines in mouse sera were quantified by an enzyme-linked immunosorbent assay.GSK3787 significantly suppressed GAC carcinogenesis in PpardTG mice. PPARδ increased Ccl20 level to chemoattract Ccr6+ immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells and T regulatory cells, but decreased CD8+ T cells in gastric tissues. GSK3787 suppressed PPARδ-induced gastric immunosuppression by inhibiting Ccl20/Ccr6 axis. Furthermore, Ccl20 protein levels increased in sera of PpardTG mice starting at the age preceding gastric tumor development and further increased with GAC progression as the mice aged. GSK3787 decreased the PPARδ-upregulated Ccl20 levels in sera of the mice.PPARδ dysregulation of Ccl20/Ccr6 axis promotes GAC carcinogenesis by remodeling gastric tumor microenvironment. CCL20 might be a potential biomarker for the early detection and progression of GAC.© 2023. The Author(s).