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Oxidative Medicine and Cellular Longevity
Volume 2019, Article ID 2647068, 15 pages
https://doi.org/10.1155/2019/2647068
Research Article

NRF1 and NRF2 mRNA and Protein Expression Decrease Early during Melanoma Carcinogenesis: An Insight into Survival and MicroRNAs

1Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
2Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
3Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland
4Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland
5Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland

Correspondence should be addressed to Peeter Karihtala; if.uluo@alathirak.reteep

Received 10 March 2019; Revised 7 June 2019; Accepted 25 June 2019; Published 4 September 2019

Guest Editor: Kanhaiya Singh

Copyright © 2019 Mari Hämäläinen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The prognostic significance of the major redox regulator nuclear factor erythroid-2-related factor (NRF2) is recognized in many cancers, but the role of NRF1 is not generally well understood in cancer. Our aim was to investigate these redox transcription factors in conjunction with redox-related microRNAs in naevi and melanoma. We characterized the immunohistochemical expression of NRF1 and NRF2 in 99 naevi, 88 primary skin melanomas, and 67 lymph node metastases. In addition, NRF1 and NRF2 mRNA and miR-23B, miR-93, miR-144, miR-212, miR-340, miR-383, and miR-510 levels were analysed with real-time qPCR from 54 paraffin-embedded naevi and melanoma samples. The immunohistochemical expression of nuclear NRF1 decreased from benign to dysplastic naevi () and to primary melanoma () and from primary melanoma to metastatic lesions (). Also, NRF1 mRNA levels decreased from benign naevi to dysplastic naevi (). Similarly, immunopositivity of NRF2 decreased from benign to dysplastic naevi () and to primary lesions (). NRF2 mRNA decreased from benign to dysplastic naevi and primary melanomas (). Analysis from the Gene Expression Omnibus datasets supported the mRNA findings. High nuclear immunohistochemical NRF1 expression in pigment cells associated with a worse survival () in patients with N0 disease at the time of diagnosis, and high nuclear NRF2 expression in pigment cells associated with a worse survival () in patients with M0 disease at the time of diagnosis. In multivariate analysis, neither of these variables exceeded the prognostic power of Breslow. The levels of miR-144 and miR-212 associated positively with ulceration ( and , respectively) while miR-510 levels associated positively with lymph node metastases at the time of diagnosis (). Furthermore, the miRNAs correlated negatively with the immunohistochemical expression of NRF1 and NRF2 but positively with their respective mRNA. Together, this data sheds new light about NFE2L family factors in pigment tumors and suggests that these factors are worth for further explorations.