Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer
Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer
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通过 NF-kappa B-CCL2 信号传导提高 neddylation 通路促进肺癌中肿瘤相关巨噬细胞浸润
DOI：
10.1038/s41388-019-0840-4
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发表时间：
2019-07-18
期刊：
影响因子：
8
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
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作者：
Zhou, Lisha;Jiang, Yanyu;Jia, Lijun
肿瘤相关巨噬细胞（Tumor-associated macrophages，TAMs）是最丰富的肿瘤基质细胞，在肿瘤免疫抑制中起重要作用，为肿瘤的发生和发展提供了适宜的微环境。然而，调节肿瘤部位中TAM浸润的机制尚未完全了解。在这里，我们发现neddylation途径的失活显著抑制TAM的浸润，从而抑制肺癌转移。RNA测序分析表明，neddylation失活抑制趋化细胞因子配体2（CCL 2）的反式激活。机制上，neddylation失活抑制Cullin-RING连接酶（CRL）的活性，并诱导其底物I κ B α的积累，以阻断NF-κ B转录活性和CCL 2反式激活。因此，neddylation失活表现出较低的单核细胞的趋化性，从而减少TAM浸润，这可以通过添加CCL 2来缓解。此外，NEDD 8的表达水平与肺腺癌中的高CCL 2表达正相关，从而使患者的总体存活率更差。总之，neddylation途径促进肺癌中CCL 2反式激活和TAMs浸润，以提供促肿瘤微环境，这验证了neddylation途径作为抗TAMs治疗策略的有希望的靶点。
Tumor-associated macrophages (TAMs) are the most abundant cancer stromal cells and play an essential role in tumor immunosuppression, providing a suitable microenvironment for cancer development and progression. However, mechanisms of regulating TAMs infiltration in tumor sites are not fully understood. Here, we show that inactivation of neddylation pathway significantly inhibits infiltration of TAMs, leading to the suppression of lung cancer metastasis. RNA-sequencing analysis revealed that neddylation inactivation suppresses the transactivation of chemotactic cytokine ligand 2 (CCL2). Mechanistically, neddylation inactivation inhibits the activity of Cullin-RING ligases (CRLs) and induces the accumulation of its substrate I kappa B alpha to block NF-kappa B transcriptional activity and CCL2 transactivation. As a result, neddylation inactivation exhibits lower chemotaxis of monocytes, thereby decreasing TAMs infiltration, which can be alleviated by CCL2 addition. Moreover, the expression level of NEDD8 is positively correlated with high CCL2 expression in lung adenocarcinoma, conferring a worse overall patient survival. Together, neddylation pathway promotes CCL2 transactivation and TAMs infiltration in lung cancer to provide a tumor-promoting microenvironment, which validates neddylation pathway as a promising target for anti-TAMs therapeutic strategies.