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 factorκB (NFκB) has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase9 (MMP9) activation. However, whether NFκB plays a role in the development and progression of melanoma in association with the OPN/MMP9 axis according to the BRAFV600E 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, MMP9 and NFκB. Significantly higher circulating levels of OPN and MMP9 were observed in the patients with melanoma when compared to the healthy donors. Similar data were obtained for NFκB p65 activity. The OPN levels did not differ significantly between melanomas with or without BRAFV600E mutation. However, as regards NFκB and MMP9, significant differences were observed between the melanomas with or without BRAFV600E mutation. To determine whether NFκB inhibition is associated with a decrease in the levels of OPN and MMP9, peripheral blood mononuclear cells from 29 patients with melanoma were treated with the NFκB inhibitor, dehydroxymethylepoxyquinomycin (DHMEQ), with or without OPN. As expected, the inhibition of NFκB induced a marked decrease in both the OPN and MMP9 levels. Furthermore, the decrease in MMP9 levels was higher among melanomas harbouring the BRAFV600E mutation. Overall, our data suggest that the activation of MMP9 is associated with the BRAFV600E mutation status. Furthermore, such an activation is mediated by NFκB, suggesting its role as therapeutic target in patients with melanoma.