An immunohistochemical study of NFE2L2, KEAP1 and 8-hydroxy-2'-deoxyguanosine and the EMT markers SNAI2, ZEB1 and TWIST1 in metastatic melanoma.

Abstract

Little is known regarding the role of redox balance regulators in metastatic melanomas, but there is some evidence for a link between epithelial-to-mesenchymal transition (EMT) and cellular redox status. We compared the immunohistochemical expression of nuclear factor erythroid-2-related factor 2 (NFE2L2), Kelch-like ECH-associated protein 1(KEAP1), 8-hydroxy-2'-deoxyguanosine (8-OHdG), TWIST1, SNAI2 and ZEB1 between primary melanomas and metastases in a cohort of 23 nevi, 66 malignant melanomas and 22 metastases. Nuclear NFE2L2 expression was higher (p=0.003) and cytoplasmic KEAP1 lower (p=0.026) in metastatic lesions than at primary sites. Nuclear NFE2L2 expression was associated with the presence of distant metastases (p=0.040) and with nuclear TWIST1 expression (p=0.002). Patients having both NFE2L2 and TWIST1 expression in nuclei had an extremely poor prognosis (p=0.0003). In multivariate analysis nuclear TWIST1 expression was an independent predictor of a poorer prognosis (HR 2.99, 95% CI 1.17-7.69; p=0.023) and the invasive TWIST1/ZEB1 phenotype showed poorer melanoma-specific survival (HR 7.28, 95% CI 2.23-23.77; p=0.001). Nuclear expression of 8-OHdG (p=0.001) was lower at metastatic sites than in primary lesions. EMT signalling and the KEAP1/NFE2L2-axis are likely to be involved in metastatic spread of malignant melanoma and also appear to have potential interactions.