Tumor-associated macrophages promote the metastasis and growth of non-small-cell lung cancer cells through NF-κB/PP2Ac-positive feedback loop.

Zhan-Wen Liang, Xin-Xin Ge, Meng-Dan Xu, Hualong Qin, Meng-Yao Wu, Meng Shen, Yan Zhang, Xiao-Meng Liu, Kai Chen, Wei Li, Weiming Duan, Songbing Qin

Cancer science 2021 Jun

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Non-small-cell lung cancer (NSCLC), with its aggressive biological behavior, is one of the most diagnosed cancers. Tumor-associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer, however the mechanisms involved are far from defined. In the present study, by developing an orthotopic NSCLC mouse model based on chronic inflammation, we proved that an inflammatory microenvironment accelerated the growth of orthotopic xenografts in vivo. Tumor-associated macrophages, the most abundant population of inflammatory cells, were identified. Treatment with macrophage-conditioned medium (MCM) promoted the growth and migration of NSCLC cells. Using bioinformatics analysis, we identified downregulated PP2Ac expression in NSCLC cells upon treatment with MCM. We further confirmed that this downregulation was executed in an NF-κB pathway-dependent manner. As IκB kinase (IKK) has been proved to be a substrate of PP2Ac, inhibition on PP2Ac could result in amplification of NF-κB pathway signaling. Overexpression of PP2Ac, or the dominant-negative forms of IKK or IκB, attenuated the acceleration of growth and metastasis by MCM. Using bioinformatics analysis, we further identified that CXCL1 and COL6A1 could be downstream of NF-κB/PP2Ac pathway. Luciferase assay and ChIP assay further confirmed the location of response elements on the promoter regions of CXCL1 and COL6A1. Elevated CXCL1 facilitated angiogenesis, whereas upregulated COL6A1 promoted proliferation and migration. © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Citation

Zhan-Wen Liang, Xin-Xin Ge, Meng-Dan Xu, Hualong Qin, Meng-Yao Wu, Meng Shen, Yan Zhang, Xiao-Meng Liu, Kai Chen, Wei Li, Weiming Duan, Songbing Qin. Tumor-associated macrophages promote the metastasis and growth of non-small-cell lung cancer cells through NF-κB/PP2Ac-positive feedback loop. Cancer science. 2021 Jun;112(6):2140-2157