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 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.

Cutaneous melanoma: From pathogenesis to therapy (Review)

“…Cutaneous melanoma is one of the most aggressive forms of skin cancer and one of the leading causes of cancer-related mortality due its metastatic power. Several studies have demonstrated that melanoma spreading is the result of genetic mutations and tumor microenvironmental alterations, characterized by the overexpression of proteins able to favor tumor invasion and surrounding infiltration ( 39 – 44 ). In particular, a key role is played by the overexpression of matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-2, that induces the degradation of the components of the extracellular matrix, thus favoring tumor cell infiltration and spreading through the bloodstream ( 40 – 42 ).…”

Association of oral dysbiosis with oral cancer development (Review)

“…This process causes the production of inflammatory mediators that can cause or facilitate mutagenesis, uncontrolled cell proliferation, angiogenesis and cell degeneration responsible for neurodegenerative disorders and cancer (70)(71)(72). In addition, bacteria are able to modulate cell proliferation through activation of the nuclear factor κB (NF-κB) and the inhibition of cell apoptosis promoting or inhibiting the development of several cancer types (73)(74)(75).…”

FoxO3a depletion accelerates cutaneous wound healing by regulating epithelial‑mesenchymal transition through β‑catenin activation

“…MMPs are considered to be a crucial family of cell migration-associated proteins that degrade collagen and different components of the ecM, contributing to Kc migration and the eMT during wound healing (26,27). Previous studies have reported that the function of MMPs is regulated by numerous factors, including transcription factors, micrornas and methylation modifications (28)(29)(30). Furthermore, further studies have demonstrated that the transcription factor Foxo3a is associated with the negative regulation of the MMP-1 and MMP-9 genes (31,32).…”