Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p
Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p
复制标题
口腔鳞癌来源的exosomes促进miR-29 a-3 p介导的M2亚型巨噬细胞极化
DOI：
10.1152/ajpcell.00366.2018
复制
发表时间：
2019-05-01
影响因子：
5.5
通讯作者：
He, Wei
中科院分区：
文献类型：
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作者：
Cai, Jinghua;Qiao, Bin;He, Wei
本研究旨在探讨口腔鳞状细胞癌源性外泌体（OSCC-Exo）介导的口腔鳞状细胞癌（OSCC）与未极化间质免疫巨噬细胞之间信号传递的机制。通过检测M1亚型或M2亚型巨噬细胞的蛋白标志物或特异性组分的水平，发现巨噬细胞的极化。将从两种OSCC细胞系中提取的外泌体与巨噬细胞共培养，以确保外泌体封闭的miR-29a-3p对巨噬细胞极化的影响，所述外泌体可能已经用micro-RNA（miR）-29a-3p抑制剂或模拟物转染。miR-29a-3p在口腔鳞癌组织中高表达，细胞因子信号转导抑制因子1（SOCS1）低表达，磷酸化信号转导和转录激活因子6（p-STAT6）高表达。在OSCC衍生的外泌体中观察到miR-29a-3p的上调。当共培养时，OSCC来源的外泌体促进M2亚型巨噬细胞极化，并且共培养的培养基促进SCC-9和CAL-27细胞的增殖和侵袭。在干扰OSCC的miR-29a-3p沉默后，SCC-9和CAL-27细胞来源的exosomes抑制M2亚型巨噬细胞极化。另一方面，巨噬细胞高表达miR-29a-3p增强M2亚型巨噬细胞极化。此外，这种巨噬细胞促进SCC-9和CAL-27的增殖和侵袭。SOCS1是miR-29a-3p的直接靶点，并可被miR-29a-3p负调控。此外，SOCS1过表达可逆转miR-29a-3p过表达诱导的巨噬细胞SOCS1/STAT6信号的活性以及OSCC的细胞增殖和侵袭。此外，巨噬细胞中过表达的SOCS1抵消了OSCC衍生的外来体在M2亚型巨噬细胞极化中的影响。外泌体封闭的miR-29a-3p促进具有异种移植物的裸鼠中的肿瘤生长。OSCC来源的exosomes促进M2亚型巨噬细胞极化是由exosomes包裹的miR-29a-3p介导的，miR-29a-3p的机制是激活巨噬细胞中的SOCS1/STAT6信号。
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.