Hanna-Riikka Hintsala1, Elina Jokinen2, Kirsi-Maria Haapasaari3, Monica Moza4, Ari Ristimäki5, Ylermi Soini6, Jussi Koivunen2, Peeter Karihtala2. 1. 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. 2. Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. 3. University of Oulu and Department of Pathology, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland. 4. Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 5. Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 6. 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.
Abstract
BACKGROUND/AIM: 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. MATERIALS AND 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. CONCLUSION: Nrf2 and 8-OHdG influence prognosis in melanoma. Copyright
BACKGROUND/AIM: 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. MATERIALS AND 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. CONCLUSION:Nrf2 and 8-OHdG influence prognosis in melanoma. Copyright
Authors: Gagan Chhabra; Chandra K Singh; Glorimar Guzmán-Pérez; Mary A Ndiaye; Kenneth A Iczkowski; Nihal Ahmad Journal: J Invest Dermatol Date: 2021-09-29 Impact factor: 7.590