Plasminogen Activator Inhibitor-1 Promotes the Recruitment and Polarization of Macrophages in Cancer
Plasminogen Activator Inhibitor-1 Promotes the Recruitment and Polarization of Macrophages in Cancer
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DOI：
10.1016/j.celrep.2018.10.082
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发表时间：
2018-11-20
期刊：
影响因子：
8.8
通讯作者：
DeClerck, Yves Albert
中科院分区：
文献类型：
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作者：
Kubala, Marta Helena;Punj, Vasu;DeClerck, Yves Albert
纤溶酶原激活物抑制剂-1（派-1）通过其促血管生成和抗凋亡活性而具有促肿瘤发生的功能。在这里，我们证明了派-1通过不同的结构域促进单核细胞/巨噬细胞的募集和M2极化。其LRP 1相互作用结构域调节巨噬细胞迁移，而其C末端uPA相互作用结构域通过激活p38 MAPK和核因子κ B（NF-κ B）以及诱导自分泌白细胞介素（IL）-6/STAT 3激活途径促进M2巨噬细胞极化。然后，我们在小鼠中的几个实验中表明，派-1的表达与致瘤性增加、M2巨噬细胞存在增加、IL-6水平升高和巨噬细胞中STAT 3磷酸化增加相关。派-1、IL-6和CD 163（M2标记物）表达之间的强正相关性也通过对许多人类癌症中转录组数据的荟萃分析发现。总之，这些数据为解释派-1在癌症中的矛盾促肿瘤发生功能的机制提供了证据。
Plasminogen activator inhibitor-1 (PAI-1) has a pro-tumorigenic function via its pro-angiogenic and anti-apoptotic activities. Here, we demonstrate that PAI-1 promotes the recruitment and M2 polarization of monocytes/macrophages through different structural domains. Its LRP1 interacting domain regulated macrophage migration, while its C-terminal uPA interacting domain promoted M2 macrophage polarization through activation of p38MAPK and nuclear factor kappa B (NF-kappa B) and induction of an autocrine interleukin (IL)-6/STAT3 activation pathway. We then show in several experiments in mice that expression of PAI-1 is associated with increased tumorigenicity, increased presence of M2 macrophages, higher levels of IL-6, and increased STAT3 phosphorylation in macrophages. Strong positive correlations between PAI-1, IL-6, and CD163 (M2 marker) expression were also found by meta-analysis of transcriptome data in many human cancers. Altogether, these data provide evidence for a mechanism explaining the paradoxical pro-tumorigenic function of PAI-1 in cancer.