Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p

Abstract

Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p. Am J Physiol Cell Physiol 316: C731–C740, 2019. First published February 27, 2019; doi:10.1152/ajpcell.00366.2018.—This study aims to explore the mechanism of the signal transmission between oral squamous cell carcinoma (OSCC) and unpolarized stromal immune macrophages mediated by OSCC-derived exosomes (OSCC-Exo). Polarization of macrophages was found by detection of the level of protein markers or specific components for M1 subtype or M2 subtype macrophages, respectively. Exosomes extracted from two OSCC cell lines, which might have been transfected with micro-RNA (miR)-29a-3p inhibitor or mimic, were cocultured with macrophages to ensure the effect of exosome-enclosed miR-29a-3p on the polarization of macrophages. miR-29a-3p is highly expressed, suppressor of cytokine signaling 1 (SOCS1) is low expressed and phosphorylated signal transduction and transcriptional activator 6 (p-STAT6) is highly expressed in OSCC tissues. Upregulation of miR-29a-3p is observed in OSCC-derived exosomes. When cocultured, OSCC-derived exosomes promote M2 subtype macrophage polarization and the medium of the coculture promotes the proliferation and invasion of SCC-9 and CAL-27 cells. After interfered silencing miR-29a-3p of OSCCs, SCC-9-and CAL-27 cell-derived exosomes inhibit M2 subtype macrophage polarization. On the other hand, cellular highly expressed miR-29a-3p of macrophages enhances M2 subtype macrophage polarization. Moreover, such macrophages promote the proliferation and invasion of SCC-9 and CAL-27. SOCS1 is a direct target for miR-29a-3p and could be negatively regulated by miR-29a-3p. Moreover, SOCS1 overexpression reverses the activity of SOCS1/STAT6 signals of macrophages and cell proliferation and invasion of OSCCs induced by miR-29a-3p overexpression. Also, overexpressed SOCS1 in macrophages counteracts the impact of OSCC-derived exosomes in M2 subtype macrophage polarization. Exosome-enclosed miR-29a-3p promotes tumor growth in nude mice with xenograft. OSCC-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p, and the mechanism by miR-29a-3p is the activity of SOCS1/STAT6 signals in macrophages.