Tumor-related exosomal circ_0001715 promotes lung adenocarcinoma cell proliferation and metastasis via enhancing M2 macrophage polarization by regulating triggering receptor expressed on myeloid cells-2

Abstract

Background: Circular RNAs (circRNAs) have been shown to mediate tumor-associated macrophages (TAMs) to regulate the development of many cancers, including lung adenocarcinoma (LUAD). However, whether circ_0001715 regulates LUAD progression by mediating TAMs polarization remains uncertain.

Methods: Monocytes (THP-1) were treated with PMA to induce M0 macrophages. M0 macrophages were incubated with LUAD cells-derived exosomes and then cocultured with LUAD cells. The levels of circ_0001715, M2 macrophage markers, microRNA (miR)-205-5p, and triggering receptor expressed on myeloid cells-2 (TREM2) were examined using quantitative real-time PCR. Flow cytometry was performed to assess M2 macrophage surface marker CD206. Cell proliferation, migration and invasion were determined using cell counting kit 8, EdU, colony formation and transwell assays. Dual-luciferase reporter assay was used to investigate the interactions between miR-205-5p and circ_0001715 or TREM2.

Results: Circ_0001715 knockdown inhibited M2 macrophage polarization and its overexpression had an opposite effect. After M0 macrophages transfected with si-circ_0001715 were cocultured with LUAD cells, the proliferation and metastasis of LUAD cells were markedly reduced. Exosomes transferred circ_0001715 between M0 macrophages and LUAD cells. Exosomal circ_0001715 promoted M2 macrophage polarization to increase LUAD cell proliferation and metastasis. In terms of mechanism, circ_0001715 sponged miR-205-5p to positively regulate TREM2. TREM2 upregulation also could promote LUAD cell proliferation and metastasis via increasing M2 macrophage polarization. In addition, TREM2 knockdown reversed the effect of exosomal circ_0001715 on M2 macrophage polarization and LUAD cell progression.

Conclusion: Exosomal circ_0001715 led to LUAD cell proliferation and metastasis by promoting M2 macrophage polarization via the miR-205-5p/TREM2 axis.

Keywords: circ_0001715; exosomes; lung adenocarcinoma; miR-205-5p; tumor-related macrophages.