Deletion of IKKβ in activated fibroblasts promotes tumor progression in melanoma

Abstract

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and play critical roles in tumorigenesis. CAFs consists of multiple subpopulations, which have diverse functions. The detailed mechanism, including the role of NF-κB, a critical transcription factor for inflammation and cell survival, in CAFs has not been adequately explored. In this study, we examined the roles of IKKβ, a key kinase for NF-κB activation, in activated CAFs by using mice (KO mice) with deletion of IKKβ in activated fibroblasts (aFbs). We found that melanoma cells implanted in KO mice showed significantly more growth than those implanted in control mice. To exclude the effects of deletion of IKKβ in cells other than aFbs, we implanted a mixture of melanoma cells and IKKβ-deleted aFbs in wild-type mice and observed that the mixture showed greater growth than a mixture of melanoma cells and normal aFbs. In exploring the mechanisms, we found that conditioned medium from IKKβ-deleted aFbs promotes the proliferation of melanoma cells, and the expression of growth arrest-specific 6 (GAS6) and hepatocyte growth factor (HGF), which are major tumor-promoting factors, was upregulated in IKKβ-deleted aFbs. These results indicated the tumor-suppressing function of IKKβ in activated CAFs.