Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Cancer Immunol Res. 2019 Feb;7(2):292-305. doi: 10.1158/2326-6066.CIR-18-0145. Epub 2018 Nov 20.
M2 polarization of macrophages is essential for their function in immunologic tolerance, which might promote tumorigenesis. However, the molecular mechanism behind the polarization process is not fully understood. Given that several lines of evidence have suggested that long noncoding RNAs (lncRNAs) could be involved in regulating immune cell differentiation and function, the current study aimed to identify the lncRNAs that specifically modulate M2 macrophage polarization. By utilizing a series of cell-based M2 macrophage polarization models, a total of 25 lncRNAs with altered expression were documented based on lncRNA microarray-based profiling assays. Among them, lncRNA-MM2P was the only lncRNA upregulated during M2 polarization but downregulated in M1 macrophages. Knockdown of lncRNA-MM2P blocked cytokine-driven M2 polarization of macrophages and weakened the angiogenesis-promoting feature of M2 macrophages by reducing phosphorylation on STAT6. Moreover, manipulating lncRNA-MM2P in macrophages impaired macrophage-mediated promotion of tumorigenesis, tumor growth and tumor angiogenesis. Collectively, our study identifies lncRNA-MM2P as a modulator required for macrophage M2 polarization and uncovers its role in macrophage-promoted tumorigenesis.
巨噬细胞 M2 极化对于其在免疫耐受中的功能至关重要，而这种免疫耐受可能会促进肿瘤发生。然而，极化过程背后的分子机制尚未完全阐明。鉴于有几条证据表明长链非编码 RNA（lncRNA）可能参与调节免疫细胞分化和功能，本研究旨在鉴定特异性调节 M2 巨噬细胞极化的 lncRNA。通过利用一系列基于细胞的 M2 巨噬细胞极化模型，根据 lncRNA 微阵列分析谱测定，共记录了 25 个表达发生改变的 lncRNA。其中，lncRNA-MM2P 是在 M2 极化过程中唯一上调但在 M1 巨噬细胞中下调的 lncRNA。lncRNA-MM2P 的敲低阻断了细胞因子驱动的巨噬细胞 M2 极化，并通过减少 STAT6 磷酸化减弱了 M2 巨噬细胞的促血管生成特征。此外，在巨噬细胞中操纵 lncRNA-MM2P 会损害巨噬细胞介导的肿瘤发生、肿瘤生长和肿瘤血管生成的促进作用。总之，本研究鉴定了 lncRNA-MM2P 作为巨噬细胞 M2 极化所必需的调节剂，并揭示了其在巨噬细胞促进肿瘤发生中的作用。
