CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling
CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling
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DOI：
10.1038/onc.2013.530
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发表时间：
2015-01-08
期刊：
影响因子：
8
通讯作者：
Michl, P.
中科院分区：
文献类型：
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作者：
Kuehnemuth, B.;Muehlberg, L.;Michl, P.
包括胰腺导管腺癌（PDAC）在内的许多实体癌的特征在于广泛的基质反应，伴有浸润性肿瘤相关巨噬细胞（TAM）。TAM在恶性肿瘤中的作用仅部分了解。此前，我们确定转录因子CUX 1是PDAC中肿瘤进展的重要介导因子。有趣的是，我们发现CUX 1不仅在肿瘤细胞中而且在TAM中高度表达。在这些数据的基础上，我们旨在阐明CUX 1在体外和体内TAM中的作用。我们使用过表达和敲低策略分析了CUX 1对细胞因子表达的影响。CUX 1对细胞因子的调节作用通过报告基因分析、DNA下拉实验和染色质免疫沉淀法进一步评估。在人胰腺癌组织和遗传小鼠模型中分析TAM中的CUX 1表达。免疫组织化学分析显示CUX 1在人PDAC组织中的TAM的不同子集中的强表达水平。此外，在PDAC的遗传小鼠模型中，其表达在肿瘤进展期间增加。分析实验表明，CUX 1下调了几种NF-κ B调节的趋化因子，如CXCL 10，这些趋化因子与M1极化和抑制血管生成和肿瘤进展有关。我们可以证明CUX 1与NF-κ B p65相互作用，导致NF-κ B p65与趋化因子启动子的结合减少。此外，CUX 1通过募集HDAC 1减少NF-κ B B p65在K310处的乙酰化。在功能上，TAM中的CUX 1表达拮抗T细胞吸引并增强体外血管生成。我们确定CUX 1作为TAMs表型和功能的重要调节因子，通过调节NF-κ B依赖性细胞因子。
Many solid cancers including pancreatic ductal adenocarcinoma (PDAC) are characterized by an extensive stromal reaction that is accompanied by infiltrating tumor-associated macrophages (TAMs). The role of TAMs in malignant tumors is only partially understood. Previously, we identified the transcription factor CUX1 as an important mediator of tumor progression in PDAC. Interestingly, we found that CUX1 is highly expressed not only in tumor cells but also in TAMs. On the basis of these data, we aimed to elucidate the effects of CUX1 in TAMs in vitro and in vivo. We analyzed the effects of CUX1 on cytokine expression using overexpression and knockdown strategies. The cytokine regulation by CUX1 was further assessed by reporter assays, DNA pulldown experiments and chromatin-immunoprecipitation. CUX1 expression in TAMs was analyzed in human pancreatic cancer tissues and in a genetic mouse model. Immunohistochemical analysis revealed strong expression levels of CUX1 in a distinct subset of TAMs in human PDAC tissues. Furthermore, its expression increased during tumor progression in a genetic mouse model of PDAC. Profiling experiments showed that CUX1 downregulates several NF-kappa B-regulated chemokines such as CXCL10, which have been associated with M1 polarization and inhibition of angiogenesis and tumor progression. We could demonstrate that CUX1 interacts with NF-kappa B p65, leading to reduced binding of NF-kappa B p65 to the chemokine promoters. In addition, CUX1 reduces acetylation of NF-kappa B p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAMs antagonizes T-cell attraction and enhances angiogenesis in vitro. We identified CUX1 as an important modulator of the TAMs phenotype and function by modulating NF-kappa B-dependent cytokines.