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NRF1 and NRF2 mRNA and Protein Expression Decrease Early during Melanoma Carcinogenesis: An Insight into Survival and
Mari Hämäläinen1,2, Hanna-Riikka Teppo1, Sini Skarp3
1Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
Oxidative Medicine and Cellular Longevity
|November 6, 2019
Summary
Investigating nuclear factor erythroid-2-related factor 1 (NRF1) and NRF2 in melanoma revealed decreased expression from benign to metastatic stages. High NRF1/NRF2 levels correlated with worse survival, though not exceeding Breslow
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The prognostic role of nuclear factor erythroid-2-related factor 2 (NRF2) is established in various cancers.
- The involvement of NRF1 in cancer progression remains less understood.
- Redox regulators and microRNAs play critical roles in cellular processes and disease development.
Purpose of the Study:
- To investigate the expression and prognostic significance of NRF1 and NRF2 in naevi and melanoma.
- To explore the relationship between NRF1, NRF2, and specific microRNAs in melanoma development.
- To assess the potential of NRF1 and NRF2 as biomarkers in skin pigment tumors.
Main Methods:
- Immunohistochemical analysis of NRF1 and NRF2 expression in 99 naevi, 88 primary melanomas, and 67 lymph node metastases.
- Quantitative real-time PCR to measure NRF1, NRF2 mRNA, and microRNA levels (miR-23B, miR-93, miR-144, miR-212, miR-340, miR-383, miR-510) in 54 samples.
- Analysis of Gene Expression Omnibus datasets to corroborate mRNA findings and correlation analysis with clinical data and survival.
Main Results:
- Nuclear NRF1 and NRF2 expression and mRNA levels significantly decreased from benign naevi to dysplastic naevi, primary melanomas, and metastatic lesions.
- High nuclear NRF1 expression was associated with worse survival in N0 disease (p=0.048), and high NRF2 with worse survival in M0 disease (p=0.033).
- Specific microRNAs (miR-144, miR-212, miR-510) correlated with melanoma ulceration and lymph node metastasis, and showed inverse correlations with NRF1/NRF2 protein but positive correlations with their mRNA.
Conclusions:
- NRF1 and NRF2 expression diminishes during melanoma progression, suggesting a role in tumor suppression or altered regulation in advanced disease.
- While NRF1 and NRF2 show prognostic associations, they did not surpass the prognostic power of Breslow depth in multivariate analysis.
- The interplay between NRF1, NRF2, and specific microRNAs warrants further investigation for their potential as diagnostic or prognostic markers in melanoma.
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