Tumor cell-derived exosomal microRNA-146a promotes non-small cell lung cancer cell invasion and proliferation by inhibiting M1 macrophage polarization

Abstract

Background: Tumor-associated macrophages (TAMs) affects the outcomes of non-small cell lung cancer (NSCLC). NSCLC cells released exosomes to suppress the antitumor activity of TAMs. MiR-146a is a critical regulator in TAM polarization. We hypothesized that NSCLC cells released exosomal miR-146a to regulate TAM polarization and thus affected its antitumor activity. Methods:We used H1299 cells-derived exosomes to stimulate THP-1 cells that was pretreated with phorbol 12-myristate 13-acetate (M0 macrophage). Flow cytometry and reverse transcription-quantitative polymerase chain reaction (PCR) were used to determine the polarization of macrophages. The conditioned medium of exosome-treated M0 cells was used to culture H1299 cells, and the Cell Counting Kit-8, Ki67, transwell and scratch wound assays were used to determine the biological behavior of H1299 cells. To investigate whether exosomal miR-146a regulates TAM macrophages through targeting tumor necrosis factor receptor-associated factor 6 (TRAF-6) and interleukin-1 receptor-associated kinase 1 (IRAK-1), we used small interfering RNA to knockdown the expressions of them.Results: Upregulation of miR-146a inhibited M1 polarization and thus impaired the antitumor activity of TAMs. Exosomes released by H1299 cells can be taken by M0 macrophage, and they upregulated the expression of miR-146a in M0 macrophage. The exosome suppresses M1 polarization by exosomal miR-146a. TRAF-6 and IRAK-1 mediated the inhibitive effects of exosomal miR-146a on M1 polarization.Conclusions: NSCLC cells released exosomal miR-146a to inhibit the expressions of TRAF-6 and IRAK-1 in TAMs, resulting in the impaired antitumor activity of TAMs. NSCLC cell-derived exosomal miR-146a represents a novel therapeutic target for NSCLC treatment.

Exosomes: efficient macrophage-related immunomodulators in chronic lung diseases

“…Consequently, tissue-resident macrophages are polarized toward an immunosuppressive phenotype ( Morrissey et al, 2021 ). Furthermore, exosomes released by non-small cell lung cancer cells inhibit the expression of TNF receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase (IRAK1) in M0 macrophages, impairing M1 polarization and diminishing their ability to eliminate tumor cells ( Yan et al, 2022 ). These findings underscore the role of tumor-derived exosomes in modulating macrophage function and shaping an immunosuppressive microenvironment that promotes tumor survival.…”

Exosomal Non-Coding RNAs: Novel Regulators of Macrophage-Linked Intercellular Communication in Lung Cancer and Inflammatory Lung Diseases

“…Exosomal miR-146a from H1299 cells can be transmitted into macrophages and then elevates miR-146a expression in macrophages. Exosomal miR-146a suppresses TNF receptor-associated factor 6 (TRAF-6) and IL-1 receptor-associated kinase 1 (IRAK-1) to repress M1 macrophage polarization, which in turn enhances cell invasion and cell proliferation in H1299 cells [ 63 ]. Hypoxic TME amplifies aggressiveness and metastasis in NSCLC.…”