title: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, I‑98125 Messina, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Guarneri
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I‑95124 Catania, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bevelacqua
authors.affiliation: Unit of Cancer Epidemiology, CRO Aviano National Cancer Institute, IRCCS, I‑33081 Aviano, Italy.
authors.forename: Jerry
authors.initials: J
authors.lastname: Polesel
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I‑95124 Catania, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Falzone
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, I‑98125 Messina, Italy.
authors.forename: Patrizia S
authors.initials: PS
authors.lastname: Cannavò
authors.affiliation: Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion 71003, Greece.
authors.forename: Demetrios A
authors.initials: DA
authors.lastname: Spandidos
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I‑95124 Catania, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Malaponte
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of General and Clinical Pathology and Oncology, University of Catania, I‑95124 Catania, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008545:Melanoma / Q000097:blood* / Q000473:pathology; D008875:Middle Aged; D016328:NF-kappa B / Q000097:blood*; D009367:Neoplasm Staging; D053495:Osteopontin / Q000097:blood*; D011379:Prognosis; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000097:blood* / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B; C506895:SPP1 protein, human; D053495:Osteopontin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9