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Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer

Oncogene volume 38, pages 5792–5804 (2019)Cite this article

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Abstract

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 IκBα to block NF-κB 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.

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Acknowledgements

The Chinese Minister of Science and Technology grant (2016YFA0501800), National Natural Science Foundation of China (Grant Nos. 81820108022, 81625018, 81572340, 81772470, 81602072, 81401893, 81702244 and 81871870), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001), and Program of Shanghai Academic/Technology Research Leader (18XD1403800), supported this work.

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  1. These authors contributed equally: Lisha Zhou, Yanyu Jiang, Xiaojun Liu

Authors and Affiliations

  1. Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Lisha Zhou, Lihui Li, Xuguang Yang, Changsheng Dong & Lijun Jia

  2. Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China

    Yanyu Jiang, Xiaojun Liu, Xiaoli Liu & Shenglin Huang

  3. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Yuli Lin & Rui He

  4. College of Life Sciences, Beijing Normal University, Beijing, China

    Yan Li & Guangwei Liu

  5. College of Pharmacy, Seoul National University, Seoul, Korea

    Jinha Yu & Lak Shin Jeong

  6. Department of Laboratory Medicine, Huaong Hospital, Fudan University, Shanghai, China

    Yanmei Zhang

  7. Department of Surgery, University of California, San Diego, USA

    Robert M. Hoffman

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Zhou, L., Jiang, Y., Liu, X. et al. Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer. Oncogene 38, 5792–5804 (2019). https://doi.org/10.1038/s41388-019-0840-4

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