Nrf2/Keap1 Pathway and Expression of Oxidative Stress Lesions 8-hydroxy-2'-deoxyguanosine and Nitrotyrosine in Melanoma

Hanna-Riikka Hintsala; Elina Jokinen; Kirsi-Maria Haapasaari; Monica Moza; Ari Ristimäki; Ylermi Soini; Jussi Koivunen; Peeter Karihtala

Nrf2/Keap1 Pathway and Expression of Oxidative Stress Lesions 8-hydroxy-2'-deoxyguanosine and Nitrotyrosine in Melanoma

Anticancer Res. 2016 Apr;36(4):1497-506.

Authors

Hanna-Riikka Hintsala¹, Elina Jokinen², Kirsi-Maria Haapasaari³, Monica Moza⁴, Ari Ristimäki⁵, Ylermi Soini⁶, Jussi Koivunen², Peeter Karihtala²

Affiliations

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.

PMID: 27069125

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.

Keywords: 8-OHdG; BRAF; Keap1; Nrf2; melanoma; nitrotyrosine; oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

8-Hydroxy-2'-Deoxyguanosine
Aged
Cell Line, Tumor
Deoxyguanosine / analogs & derivatives
Deoxyguanosine / metabolism
Female
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Kaplan-Meier Estimate
Kelch-Like ECH-Associated Protein 1
Male
Melanoma / metabolism*
NF-E2-Related Factor 2 / metabolism*
Oxidative Stress
Proto-Oncogene Proteins B-raf / metabolism
Signal Transduction
Skin Neoplasms / metabolism*
Tyrosine / analogs & derivatives*
Tyrosine / metabolism

Substances

Intracellular Signaling Peptides and Proteins
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
3-nitrotyrosine
Tyrosine
8-Hydroxy-2'-Deoxyguanosine
BRAF protein, human
Proto-Oncogene Proteins B-raf
Deoxyguanosine