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

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 (p < 0.001) and to primary melanoma (p < 0.001) and from primary melanoma to metastatic lesions (p = 0.012). Also, NRF1 mRNA levels decreased from benign naevi to dysplastic naevi (p = 0.034). Similarly, immunopositivity of NRF2 decreased from benign to dysplastic naevi (p = 0.02) and to primary lesions (p = 0.018). NRF2 mRNA decreased from benign to dysplastic naevi and primary melanomas (p = 0.012). Analysis from the Gene Expression Omnibus datasets supported the mRNA findings. High nuclear immunohistochemical NRF1 expression in pigment cells associated with a worse survival (p = 0.048) in patients with N0 disease at the time of diagnosis, and high nuclear NRF2 expression in pigment cells associated with a worse survival (p = 0.033) 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 (p = 0.012 and p = 0.027, respectively) while miR-510 levels associated positively with lymph node metastases at the time of diagnosis (p = 0.004). 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.

Metapristone(RU486 derivative) inhibits endometrial cancer cell progress through regulating miR-492/Klf5/Nrf1 axis

“…The specific biological function of Klf5 is considered as transcription factor to regulate cell proliferation, apoptosis, migration, and differentiation [30,31]. The other study also indicated that Nrf1 was involved in the melanoma carcinogenesis [32]. Hence, our results…”

Metapristone (RU486 derivative) inhibits endometrial cancer cell progress through regulating miR-492/Klf5/Nrf1 axis

“…The speci c biological function of Klf5 is considered as transcription factor to regulate cell proliferation, apoptosis, migration, and differentiation [33,34]. The other study also indicated that Nrf1 was involved in the melanoma carcinogenesis [35]. Hence, our results provided a new research direction for the research of Klf5 and Nrf1.…”

Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression

“…Among these miRNAs, miR-144-3p played an important role in the regulation of NRF2. Targeting NRF2 by miR-144-3p inhibited tumor progression in melanoma and acute myeloid leukemia 86 , and increased the sensitivity of lung cancer cells to cisplatin 87 , indicating the role of miR‑144‑3p in oxidative homeostasis. Other miRNAs that targeted NRF2 include miR-144 , miR-153 , miR-200c , and miR-212-3p , although their effects have not been explored 82 , 88 – 90 .…”