Gastric Cancer Cell-Derived Exosomes Induce Macrophage M2 Polarization by Delivering circSMARCC1 to Promote Gastric Cancer Progression

Abstract

Exosomes, the cargo of circRNA, are crucial in cancer cell–tumor microenvironment communication. circSMARCC1 exerts a pro-tumor effect. However, this role has not been previously reported in gastric cancer (STAD). This study explores the role of STAD cell-derived exosomal circSMARCC1 in promoting macrophage M2 polarization. In this study, exosomes from the peripheral blood of STAD patients and AGS cells were extracted and identified. THP-1 cells were differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) and polarized to the M2 phenotype by IL-4 and IL-13. circSMARCC1 expression was analyzed in STAD tissues, cell lines, and patient-derived exosomes. The biological function of circSMARCC1 in STAD cells was evaluated by CCK-8, EdU, and Transwell assays. The role of circSMARCC1 and U2 small nuclear RNA auxiliary factor 2 (U2AF2) in regulating macrophage M2 polarization was verified by bioinformatics methods, qRT-PCR, Western blot, ELISA, and a nude mouse tumor-bearing model. Our findings demonstrated that circSMARCC1 was upregulated in STAD and associated with macrophage immune infiltration. circSMARCC1 knockdown suppressed the malignant phenotypes of STAD cells and M2 macrophage polarization, whereas its overexpression led to the contrary result. Animal experiments further confirmed circSMARCC1 regulated tumor growth and macrophage M2 polarization. Importantly, exosomal circSMARCC1 in STAD patients was increased. Knockdown of circSMARCC1 in AGS cells reduced its level in secreted exosomes and inhibited M2 polarization, whereas overexpression produced the opposite effect. Mechanistically, circSMARCC1 upregulated U2AF2 expression through exosomes to promote macrophage M2 polarization. Collectively, STAD cell-derived exosomes induced macrophage M2 polarization to promote STAD progression through circSMARCC1.