Abstract
Clinical and experimental evidence indicates that macrophages could promote solid-tumor progression and metastasis. However, the mechanisms underlying this process remain unclear. Here we show that yes-associated protein 1 (YAP1), a transcriptional regulator that controls tissue growth and regeneration, has an important role in tumor necrosis factor α (TNF α)-induced breast cancer migration. Mechanistically, macrophage conditioned medium (CM) or TNFα triggers IκB kinases (IKKs)-mediated YAP phosphorylation and activation in breast cancer cells. We further found that TNFα or macrophage CM treatment increases the interaction between p65 and YAP. Chromatin immunoprecipitation (ChIP) assay shows that YAP/TEAD (TEA domain family member) and p65 proteins synergistically regulate the transcription of hexokinase 2 (HK2), a speed-limiting enzyme in glycolysis, and promotes TNFα-induced or macrophage CM-induced cell migration. Together, our findings indicate an important role of TNFα-IKK-YAP/p65-HK2 signaling axis in the process of inflammation-driven migration in breast cancer cells, which reveals a new molecular link between inflammation and breast cancer metastasis.
Highlights
Tumor microenvironment consists of heterogeneous components including extracellular matrix, tumor-associated stromal cells and a myriad of signaling molecules,[1] which can significantly influence tumor growth and metastasis.[2]
Macrophage conditioned medium (CM) treatment promotes the transactivation of yes-associated protein (YAP)
The results showed that macrophage CM significantly increased the migration of MCF7 cells, whereas knockdown of YAP rescued this phenomenon (Figures 1a and b)
Summary
Tumor microenvironment consists of heterogeneous components including extracellular matrix, tumor-associated stromal cells and a myriad of signaling molecules,[1] which can significantly influence tumor growth and metastasis.[2] Macrophages in tumor microenvironment have a key role in promoting tumor metastasis.[3]. TNFα activates IκB kinases (IKKs), c-Jun N-terminal kinase and mitogenactivated protein kinase signaling to stimulate the nuclear translocation of transcription factors including activator protein[1] (AP-1) and nuclear factor kappa B (NF-κB) via TNF receptor 1 (TNFR1).[6] TNFα promotes the expression of genes involved in tumor invasion and metastasis such as interleukin-8 (IL-8), monocyte chemotactic protein-1 and matrix metalloproteinase, enhancing tumor progression.[6,7]
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