Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Lerner Research Institute Imaging Core, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Int J Mol Sci. 2020 Oct 19;21(20):7716. doi: 10.3390/ijms21207716.
Ezrin links the cytoskeleton to cell surface integrins and plasma membrane receptors, contributing to the proliferative and metastatic potential of cancer cells. Elevated ezrin expression in several cancers is associated with poor outcomes. Tumor cell ezrin expression and function have been investigated in depth; however, its role in macrophages and other tumor microenvironment cells remains unexplored. Macrophages profoundly influence tumorigenesis, and here we explore ezrin's influence on tumor-promoting macrophage functions. Ezrin knockdown in THP-1 macrophages reveals its important contribution to adhesion to endothelial cells. Unexpectedly, ezrin is essential for the basal and breast cancer cell-stimulated THP-1 expression of mRNA that encodes integrin CD11b, critical for cell adhesion. Ezrin skews the differentiation of THP-1 macrophages towards the pro-tumorigenic, M2 subtype, as shown by the reduced expression of , , and mRNAs following ezrin knockdown. Additionally, macrophage ezrin contributes to the secretion of factors that stimulate tumor cell migration, invasion, and clonogenic growth. Lastly, THP-1 ezrin is critical for the expression of mRNAs encoding vascular endothelial growth factor (VEGF)-A and matrix metalloproteinase (MMP)-9, consistent with pro-tumorigenic function. Collectively, our results provide insight into ezrin's role in tumorigenesis, revealing a bidirectional interaction between tumor-associated macrophages and tumor cells, and suggest myeloid cell ezrin as a target for therapeutic intervention against cancer.
埃兹蛋白将细胞骨架与细胞表面整合素和质膜受体连接起来，有助于癌细胞的增殖和转移潜能。几种癌症中埃兹蛋白的高表达与不良预后相关。肿瘤细胞埃兹蛋白的表达和功能已被深入研究；然而，其在巨噬细胞和其他肿瘤微环境细胞中的作用仍未被探索。巨噬细胞深刻地影响肿瘤发生，在这里我们探讨埃兹蛋白对促进肿瘤的巨噬细胞功能的影响。THP-1 巨噬细胞中的埃兹蛋白敲低揭示了其对与内皮细胞黏附的重要贡献。出乎意料的是，埃兹蛋白对于基础状态和乳腺癌细胞刺激的 THP-1 细胞整合素 CD11b 的 mRNA 表达是必需的，CD11b 对于细胞黏附至关重要。埃兹蛋白使 THP-1 巨噬细胞向促肿瘤发生的 M2 亚型分化，这表现为埃兹蛋白敲低后 、 和 mRNAs 的表达减少。此外，巨噬细胞埃兹蛋白有助于刺激肿瘤细胞迁移、侵袭和集落生长的因子的分泌。最后，THP-1 埃兹蛋白对于编码血管内皮生长因子 (VEGF)-A 和基质金属蛋白酶 (MMP)-9 的 mRNAs 的表达至关重要，这与促肿瘤发生的功能一致。总之，我们的结果提供了埃兹蛋白在肿瘤发生中的作用的见解，揭示了肿瘤相关巨噬细胞和肿瘤细胞之间的双向相互作用，并表明髓样细胞埃兹蛋白作为针对癌症的治疗干预的靶标。
