NF-κB inhibition is associated with OPN/MMP-9 downregulation in cutaneous melanoma

Abstract

The development of cutaneous melanoma is influenced by genetic factors, including BRAF mutations and environmental factors, such as ultraviolet exposure. Its progression has been also associated with the involvement of several tumour microenvironmental molecules. Among these, nuclear factor-κB (NF-κB) has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) activation. However, whether NF-κB plays a role in the development and progression of melanoma in association with the OPN/MMP-9 axis according to the BRAF ^V600E mutation status has not been investigated in detail to date. Thus, in the present study, in order to shed light on this matter, 148 patients with melanoma and 53 healthy donors were recruited for the analysis of OPN, MMP-9 and NF-κB. Significantly higher circulating levels of OPN and MMP-9 were observed in the patients with melanoma when compared to the healthy donors. Similar data were obtained for NF-κB p65 activity. The OPN levels did not differ significantly between melanomas with or without BRAF ^V600E mutation. However, as regards NF-κB and MMP-9, significant differences were observed between the melanomas with or without BRAF ^V600E mutation. To determine whether NF-κB inhibition is associated with a decrease in the levels of OPN and MMP-9, peripheral blood mononuclear cells from 29 patients with melanoma were treated with the NF-κB inhibitor, dehydroxymethylepoxyquinomycin (DHMEQ), with or without OPN. As expected, the inhibition of NF-κB induced a marked decrease in both the OPN and MMP-9 levels. Furthermore, the decrease in MMP-9 levels was higher among melanomas harbouring the BRAF ^V600E mutation. Overall, our data suggest that the activation of MMP-9 is associated with the BRAF ^V600E mutation status. Furthermore, such an activation is mediated by NF-κB, suggesting its role as therapeutic target in patients with melanoma.