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首页> 外文期刊>Molecular and Cellular Biology >Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells
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Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells

机译：C /EBPβ和胰岛素样生长因子I在巨噬细胞肿瘤细胞中的关键生存作用

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One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf-transformed macrophages require the transcription factor C/EBPβ to prevent cell death. In contrast to wild-type cells, C/EBPβ?/? macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBPβ-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBPβ stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBPβ. Serological neutralization of IGF-I in C/EBPβ+/+ tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I?/? mice were GF dependent, similar to C/EBPβ-deficient cells. Forced expression of either C/EBPβ or IGF-I in C/EBPβ?/? bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBPβ is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.
机译：白血病细胞的标志之一是它们在没有外源生长因子（GFs）的情况下增殖和存活的能力。但是，尚未完全了解髓样肿瘤细胞逃避凋亡所用的分子机制。在这里我们报告Myc / Raf转化的巨噬细胞需要转录因子C /EBPβ来防止细胞死亡。与野生型细胞相反，C /EBPβα/β巨噬细胞的存活完全依赖于巨噬细胞集落刺激因子或粒细胞-巨噬细胞集落刺激因子，并且在体内显示出致瘤性受损。基因芯片分析显示，C /EBPβ缺陷细胞表达的生存因子胰岛素样生长因子I（IGF-1）的水平明显降低。 C /EBPβ的过表达刺激了 IGF-I 启动子的转录，表明 IGF-I 是C /EBPβ的直接转录靶标。 C /EBPβ + / + 肿瘤细胞培养物中IGF-1的血清中和可诱导细胞凋亡，表明IGF-1在这些细胞中起自分泌存活因子的作用。 IGF-I ？/？小鼠衍生的巨噬细胞肿瘤细胞是GF依赖性的，类似于C /EBPβ缺陷型细胞。在C /EBPβ？/？骨髓细胞中强迫表达C /EBPβ或IGF-I恢复了Myc / Raf诱导的转化，并允许肿瘤生长而没有外源性GFs。因此，我们的发现证明C /EBPβ对于巨噬细胞的致癌转化是至关重要的，并且至少部分地通过调节存活因子IGF-1的表达来起作用。

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