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 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, 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 BRAFV600E mutation.,However, as regards NF-κB and MMP-9, significant differences were observed between the melanomas with or without BRAFV600E 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 BRAFV600E mutation.,Overall, our data suggest that the activation of MMP-9 is associated with the BRAFV600E mutation status.,Furthermore, such an activation is mediated by NF-κB, suggesting its role as therapeutic target in patients with melanoma.
Patients with early stage, radial growth phase (RGP) melanoma have a 97% survival rate; however, when the melanoma progresses to the invasive vertical growth phase (VGP), survival rates decrease to 15%.,The targets of many clinical trials are the known genetic and molecular mechanisms involved in melanoma progression, with the most common oncogenic mutation being the BRAFV600E.,However, less than half of melanomas harbor this mutation, and consequently, do not respond to the current BRAF targeted treatments.,It is therefore critical to elucidate alternative mechanisms regulating melanoma progression.,Increased expression of the chemokine receptor, CXCR3, on melanoma cells is correlated with increased metastasis and poor patient outcomes, suggesting a role for CXCR3 in the RGP to VGP transition.,We found that endogenous CXCR3 can be induced in two RGP cell lines, BOWES (BRAFWT) and WM35 (BRAFV600E), with in vitro environmental stress and nutrient deprivation.,Signaling via induced endogenous CXCR3 is linked with IL-8 expression in BOWES cells.,Ectopic overexpression of CXCR3 in BOWES cells leads to increased ligand-mediated phERK, cellular migration, and IL-8 expression in vitro, and to increased tumorigenesis and lymph node metastasis in vivo.,Our results demonstrate that, in BRAFWT melanomas, CXCR3 signaling mediates significant increases in IL-8 expression, suggesting that CXCR3 expression and signaling may represent a transformative event that drives the progression of BRAFWT melanomas.,Implications: Expression of CXCR3 on BRAFWT melanoma cells may be a mediator of melanoma progression.