Circular RNAs (circRNAs) play important roles in gastric cancer progression but the regulatory role of circRNAs in controlling macrophage function remains elusive. Exosomes serve as cargo for circRNAs and play a crucial role as mediators in facilitating communication between cancer cells and the tumor microenvironment. In this study, we found that circATP8A1, a previously unreported circular RNA, is highly expressed in both gastric cancer tissues and exosomes derived from plasma. Increased circATP8A1 was associated with advanced TNM stage and worse prognosis in patients with gastric cancer. We showed that the circATP8A1 knockdown significantly inhibited gastric cancer proliferation and invasion in vitro and in vivo. Functionally, exosome circATP8A1 induced the M2 polarization of macrophages through the STAT6 pathway instead of the STAT3 pathway. Mechanistically, circATP8A1 was shown to activate the STAT6 pathway through competitive binding to miR-1-3p, as confirmed by Fluorescence In Situ Hybridization (FISH), RNA immunoprecipitation, RNA pulldown, and Luciferase reporter assays. The reversal of circATP8A1-induced STAT6 pathway activation and macrophage polarization was observed upon blocking miR-1-3p. Macrophages treated with exosomes from gastric cancer cells overexpressing circATP8A1 were able to promote gastric cancer migration, while knockdown of circATP8A1 reversed these effects in vivo. In summary, exosome-derived circATP8A1 from gastric cancer cells induce macrophages M2 polarization via the circATP8A1/miR-1-3p/STAT6 axis, and tumor progression. Our results highlight circATP8A1 as a potential prognostic biomarker and therapeutic target in gastric cancer.

中文翻译：

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外泌体circATP8A1通过调节miR-1-3p/STAT6轴诱导巨噬细胞M2极化促进胃癌进展

环状RNA（circRNA）在胃癌进展中发挥重要作用，但circRNA在控制巨噬细胞功能中的调节作用仍然难以捉摸。外泌体作为 circRNA 的货物，在促进癌细胞与肿瘤微环境之间的沟通方面发挥着至关重要的介质作用。在这项研究中，我们发现circATP8A1（一种以前未报道的环状RNA）在胃癌组织和血浆来源的外泌体中高表达。circATP8A1 增加与胃癌患者的晚期 TNM 分期和较差的预后相关。我们发现，circATP8A1 敲低可在体外和体内显着抑制胃癌的增殖和侵袭。从功能上讲，外泌体 circATP8A1 通过 STAT6 途径而不是 STAT3 途径诱导巨噬细胞的 M2 极化。从机制上讲，经荧光原位杂交 (FISH)、RNA 免疫沉淀、RNA Pulldown 和荧光素酶报告基因检测证实，circATP8A1 通过与 miR-1-3p 竞争性结合来激活 STAT6 通路。阻断 miR-1-3p 后观察到 circATP8A1 诱导的 STAT6 通路激活和巨噬细胞极化的逆转。用来自过度表达 circATP8A1 的胃癌细胞的外泌体处理的巨噬细胞能够促进胃癌迁移，而 circATP8A1 的敲低在体内逆转了这些作用。总之，来自胃癌细胞的外泌体来源的 circATP8A1 通过 circATP8A1/miR-1-3p/STAT6 轴诱导巨噬细胞 M2 极化，并诱导肿瘤进展。我们的结果强调 circATP8A1 作为胃癌的潜在预后生物标志物和治疗靶点。