Nsclc-derived exosomal hsa_circ_0003026 promotes tumor growth through macrophage M2 polarization via...

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. This study aimed to investigate the role of exosomal hsa_circ_0003026 in NSCLC progression and its underlying mechanism, particularly focusing on its effect on tumor-associated macrophage polarization.

Exosomes were isolated from serum samples of NSCLC patients and cell lines, and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), and western blot. The expression of hsa_circ_0003026 was analyzed by qRT-PCR. Macrophage polarization was assessed by examining M1/M2 markers through qRT-PCR, Western blot, and ELISA. The interaction between hsa_circ_0003026 and hsa-miR-1183, as well as between hsa-miR-1183 and XRN2, was verified using dual-luciferase reporter, RIP, and RNA pull-down assays. The effects on tumor growth were evaluated using EdU proliferation assay, CCK-8 assay, and xenograft mouse models.

Exosomal hsa_circ_0003026 levels were significantly elevated in both NSCLC patients' serum and cell lines compared to controls. A549 cell-derived exosomes induced macrophage M2 polarization, which was dependent on hsa_circ_0003026. Mechanistically, hsa_circ_0003026 functioned as a molecular sponge for hsa-miR- 1183, thereby regulating XRN2 expression. Knockdown of hsa_circ_0003026 in exosomes significantly impaired their ability to induce M2 polarization, while inhibition of hsa-miR-1183 or overexpression of XRN2 rescued this effect. Furthermore, coculture with exosome-treated macrophages promoted NSCLC growth both in vitro and in vivo, which was attenuated when hsa_circ_0003026 was silenced.

Our findings reveal a novel mechanism whereby NSCLC-derived exosomal hsa_circ_0003026 promotes tumor progression by inducing M2 macrophage polarization through the hsa-miR-1183/XRN2 axis, suggesting potential therapeutic strategies for NSCLC treatment.