Journal
AGING-US
Volume 11, Issue 19, Pages 8623-8641Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102351
Keywords
TRIM59; tumor-associated-macrophages; M2 phenotype; melanoma; metastasis
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Funding
- National Natural Science Foundation of China [81571530, 31570934]
- Fundamental Research Funds for the Central Universities of China
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The culture supernatant from macrophages overexpressing TRIM59 has a cytotoxic effect on melanoma, but the mechanism remains unclear. To investigate whether deletion of TRIM59 in macrophages affects the metastatic potential of melanoma cells, we polarized control and TRIM59-deficient bone marrow-derived macrophages to the M2 phenotype and collected the respective conditioned media (CM). Exposure to CM from TRIM59(-/-)-M2 cultures significantly promoted migration and invasion by B16-F0 and B16-F10 cells. Cytokine profiling indicated a (similar to)15-fold increase in TNF-alpha production in CM from TRIM59(-/-)-M2 cultures, and neutralizing TNF-alpha activity abrogated the referred stimulatory effects on cell motility. Transcriptome analysis revealed significant upregulation of MMP-9 and Madcam1 in melanoma cells exposed to TRIM59(-/-)-M2 CM. Inhibitory experiments determined that these changes were also TNF-alpha-dependent and mediated by activation of ERK signaling. Independent knockdown of MMP9 and Madcam1 in B16-F10 cells impeded epithelial-mesenchymal transition and inhibited subcutaneous tumor growth and formation of metastatic lung nodules in vivo. These data suggest TRIM59 expression attenuates the tumor-promoting effect of tumor-associated macrophages, most of which resemble the M2 phenotype. Moreover, they highlight the relevance of TRIM59 in macrophages as a potential regulator of tumor metastasis and suggest TRIM59 could serve as a novel target for cancer immunotherapy.
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