Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, CA 90033, USA; The Saban Research Institute of Children's Hospital, Los Angeles, CA 90027, USA.
Division of Hematology, Department of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Cell Rep. 2018 Nov 20;25(8):2177-2191.e7. doi: 10.1016/j.celrep.2018.10.082.
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 κB (NF-κB) 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.
纤溶酶原激活物抑制剂-1（PAI-1）通过其促血管生成和抗细胞凋亡活性具有促肿瘤发生作用。在这里，我们证明 PAI-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 LRP1 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 p38MAPK 和核因子κB（NF-κB）并诱导自分泌白细胞介素（IL）-6/STAT3 激活途径促进 M2 巨噬细胞极化。然后，我们在几项小鼠实验中表明，PAI-1 的表达与肿瘤发生能力增加、M2 巨噬细胞的存在增加、IL-6 水平升高以及巨噬细胞中 STAT3 磷酸化增加有关。通过对许多人类癌症的转录组数据进行荟萃分析，还发现了 PAI-1、IL-6 和 CD163（M2 标志物）表达之间的强正相关。总之，这些数据为解释 PAI-1 在癌症中悖论性促肿瘤发生功能的机制提供了证据。
