title: 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.
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Cancer Center of Eastern Finland and Department of Clinical Pathology, Kuopio University Hospital.|Department of Pathology, University of Oulu, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland. Hanna-Riikka.Hintsala@oulu.fi.|Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Hanna-Riikka
authors.initials: HR
authors.lastname: Hintsala
authors.affiliation: Department of Pathology, University of Oulu, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: Kirsi-Maria
authors.initials: KM
authors.lastname: Haapasaari
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Cancer Center of Eastern Finland and Department of Clinical Pathology, Kuopio University Hospital.
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.affiliation: Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Peeter
authors.initials: P
authors.lastname: Karihtala
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D015996:Survival Rate; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine