NRF3 Decreases during Melanoma Carcinogenesis and Is an Independent Prognostic Marker in Melanoma

The prognostic significance of the major redox regulator, nuclear factor erythroid-2-related factor 2 (NRF2), is recognized in many cancers, but the role of NRF3 is not studied. Analysis from the Gene Expression Omnibus datasets showed that NRF3 mRNA levels increased from benign to dysplastic naevi (p = 0.04). We characterized the immunohistochemical expression of NRF3 in 81 naevi, 67 primary skin melanomas, and 51 lymph node metastases. The immunohistochemical expression of cytoplasmic NRF3 decreased from benign to dysplastic naevi (p < 0.001) and further to primary melanomas (p < 0.001). High cytoplasmic NRF3 protein expression in pigment cells of the primary melanomas associated with worse melanoma-specific survival in multivariate analysis, specifically in the subgroup of patients with the lymph node metastases at the time of diagnosis (hazard ratio 3.179; 95% confidence interval 1.065-9.493; p = 0.038). Intriguingly, we did not observe associations between NRF3 and the traditional prognostic factors such as Breslow thickness, ulceration, or stage. Together, this data represents the primary description about the role of NRF3 in pigment tumours that is worthy of further explorations.