TRAF6 Activates Fibroblasts to Cancer-Associated Fibroblasts through FGF19 in Tumor Microenvironment to Benefit the Malignant Phenotype of Melanoma Cells

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment and mediate tumor progression in various cancers. A previous study demonstrated that TRAF6 promotes the malignant phenotype of melanoma cells. However, the role of TRAF6 in melanoma CAFs remains unclear. In this study, we found that TRAF6 was significantly upregulated in CAFs adjacent to melanoma cells. Functional assays showed that TRAF6 promoted fibroblast proliferation and migration as well as MMP and alpha-SMA expression. Moreover, the expression of TRAF6 in fibroblasts promoted the malignant phenotype of melanoma cells in vitro and in vivo. Meanwhile, the intervention of TRAF6 expression in melanoma cells affected the activation of CAFs. We found that FGF19 was a key cytokine regulated by TRAF6 through NF-kappa B1 using luciferase assay and chromatin immunoprecipitation in melanoma cells. Because plasma FGF19 levels are elevated in patients with melanoma, it may significantly induce fibroblast activation in vitro and in vivo. Taken together, our results support that TRAF6 is a key molecule that mediates the interaction between melanoma cells and stromal fibroblasts, suggesting that TRAF6 is a potentially promising target in melanoma therapy.