The prognostic significance of the major redox regulator nuclear factor erythroid-2-related factor (NRF2) is recognized in many
cancers, but the role of NRF1 is not generally well understood in
cancer. Our aim was to investigate these redox
transcription factors in conjunction with redox-related
microRNAs in naevi and
melanoma. We characterized the immunohistochemical expression of NRF1 and NRF2 in 99 naevi, 88 primary skin
melanomas, and 67
lymph node metastases. In addition, NRF1 and NRF2
mRNA and miR-23B, miR-93, miR-144, miR-212, miR-340, miR-383, and miR-510 levels were analysed with real-time qPCR from 54
paraffin-embedded naevi and
melanoma samples. The immunohistochemical expression of nuclear NRF1 decreased from benign to dysplastic naevi (p < 0.001) and to primary
melanoma (p < 0.001) and from primary
melanoma to metastatic lesions (p = 0.012). Also, NRF1
mRNA levels decreased from benign naevi to dysplastic naevi (p = 0.034). Similarly, immunopositivity of NRF2 decreased from benign to dysplastic naevi (p = 0.02) and to primary lesions (p = 0.018). NRF2
mRNA decreased from benign to dysplastic naevi and primary
melanomas (p = 0.012). Analysis from the Gene Expression Omnibus datasets supported the
mRNA findings. High nuclear immunohistochemical NRF1 expression in pigment cells associated with a worse survival (p = 0.048) in patients with N0 disease at the time of diagnosis, and high nuclear NRF2 expression in pigment cells associated with a worse survival (p = 0.033) in patients with M0 disease at the time of diagnosis. In multivariate analysis, neither of these variables exceeded the prognostic power of Breslow. The levels of miR-144 and miR-212 associated positively with ulceration (p = 0.012 and p = 0.027, respectively) while miR-510 levels associated positively with
lymph node metastases at the time of diagnosis (p = 0.004). Furthermore, the
miRNAs correlated negatively with the immunohistochemical expression of NRF1 and NRF2 but positively with their respective
mRNA. Together, this data sheds new light about NFE2L family factors in pigment
tumors and suggests that these factors are worth for further explorations.