title: Nrf2/Keap1 Pathway and Expression of Oxidative Stress Lesions 8-hydroxy-2'-deoxyguanosine and Nitrotyrosine in Melanoma.
abstract: OBJECTIVE
  Increased expression and prognostic significance of major redox regulator nuclear factor erythroid-2-related factor (Nrf2) is recognized in many cancers. Our aim was to investigate the role of oxidative stress markers in melanoma.
  
  
  METHODS
  We characterized the immunohistochemical expression of Nrf2, kelch-like ECH-associated protein 1 (Keap1), BRAF(V600E), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine in 36 nevi, 14 lentigo maligna and 71 malignant melanomas. We measured Nrf2 expression in melanoma cell lines and conducted cytotoxicity assays combining BRAF/NRAS ablation and H2O2treatment.
  
  
  RESULTS
  Nuclear Nrf2 expression in melanoma correlated with deeper Breslow (p<0.0005), invasive phenotype (Clark III-V) (p=0.011), nodular growth (p=0.001) and worse melanoma-specific survival (p=0.008). Absence of 8-OHdG in the endothelium was a greater significant predictor of poor prognosis (p=0.024) than ulceration (p=0.17) and had a similar impact on prognosis as Breslow (p=0.024). A decrease of Nrf2 followed the BRAF/NRAS inhibition, but combination of inhibitor with H2O2did not increase cytotoxicity.
  
  
  CONCLUSIONS
  Nrf2 and 8-OHdG influence prognosis in melanoma.
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, Kuopio, Finland University of Oulu and Department of Pathology, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland Hanna-Riikka.Hintsala@oulu.fi.
authors.forename: Hanna-Riikka
authors.initials: HR
authors.lastname: Hintsala
authors.affiliation: Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Jokinen
authors.affiliation: University of Oulu and Department of Pathology, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: Kirsi-Maria
authors.initials: KM
authors.lastname: Haapasaari
authors.affiliation: Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Monica
authors.initials: M
authors.lastname: Moza
authors.affiliation: Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
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, Kuopio, Finland.
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: Jussi
authors.initials: J
authors.lastname: Koivunen
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; D045744:Cell Line, Tumor; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D003849:Deoxyguanosine
keywords: 8-OHdG; BRAF; Keap1; Nrf2; melanoma; nitrotyrosine; oxidative stress