Nrf2 protein in melanoma progression, as a new means of treatment

Abstract

Melanoma is a potentially lethal form of skin cancer resulting from the unlimited proliferation of melanocytes. Melanocytic lineage appears to have a greater rate of reactive oxygen species (ROS) production, possibly as a result of exposure to ultraviolet (UV) light and the production of melanin. It has been established that nuclear factor erythroid 2‐related factor 2 (Nrf2) serves as a master regulator of the cellular response to oxidative stresses. Recent research has shown that the Nrf2 and its critical negative regulator Kelch‐like ECH‐associated protein 1 (Keap1) are misregulated in melanoma, and the Keap1‐Nrf2 pathway has emerged as a promising new target for treating and preventing melanoma. In melanoma, Nrf2 may either limit tumor growth or promote its development. This review covers a wide range of topics, including the dual functions played by the Keap1‐Nrf2 signaling pathway in melanoma and the most recent targeting techniques of the Nrf2.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…Similar dual roles of NRF2 in protection against melanomagenesis and promotion of tumor growth were discussed recently [ 76 , 650 ]. Similar dual anti- and pro-cancerogenic functions of NRF2 have been described for other cancers, with the latter suggesting hijacking of NRF2 by cancer cells for their survival [ 651 ].…”

“…Malignant transformation of melanocytes with further progression to advanced stages, collectively called melanomagenesis, is initiated and driven by environmental, genetic (inheritable), constitutional, and epigenetic factors, as well as by acquired mutations with the accumulation of genomic changes further amplified by local and systemic neuroimmunoendocrine factors affecting progression of the disease [ 1 , 2 , 4 , 6 , 9 , 11 , 12 , 13 , 14 , 30 , 32 , 50 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Since these factors have been discussed in many review articles, we will only provide a brief overview of them.…”

“…Malignant transformation of melanocytes and further progression to advanced stages of melanoma are driven by environmentally induced somatic mutations in a cellular, tissue, and systemic context-dependent fashion as discussed in numerous reviews [ 1 , 2 , 4 , 6 , 10 , 11 , 18 , 30 , 36 , 37 , 74 , 76 , 77 , 82 , 86 , 126 , 127 , 128 , 129 , 130 ]. Therefore, our overview on this topic will be brief.…”

“…Others include protein, phosphatase and tensin homolog ( PTEN ), and KIT , affecting cell metabolism, survival, and proliferation, ARID1 and 2 (AT-rich interaction domain 1 and 2) affecting cell identity, TP53 (tumor suppressor gene affecting resistance to apoptosis), TERT affecting replicative lifespan, and cell cycle control gene CDKN2A . There are several other mutations affecting melanoma progression in cutaneous melanoma exposed to sun [ 1 , 2 , 4 , 6 , 10 , 11 , 18 , 30 , 36 , 37 , 74 , 76 , 77 , 82 , 126 , 127 ] from which desmoplastic melanoma differ not in mutational load but in genes affected [ 36 , 132 ]. Acral melanomas, having no direct association with sun exposure, although having mutations in BRAF , NRAS , NF1 , and KIT , show a lighter and different mutational burden in comparison to low-CSD or high-CSD melanomas [ 6 , 10 , 31 , 32 , 79 , 133 , 134 , 135 , 136 ].…”

“…The pathological and clinical staging allows precise prediction of the natural history of the disease, including overall survival (OS) and disease-free survival (DF) times, and when supplemented by ancillary studies (IHC) or molecular testing (GP, GEP, NEGS) form a basis for an educated selection of appropriate therapeutic approaches. It must be noted that the staging of melanoma would likely be modified and/or supplemented by deposited RNA sequencing data, proteomic data, or metabolomic data at publicly available databases with implications for future therapy [ 1 , 11 , 18 , 30 , 48 , 74 , 75 , 76 , 77 , 79 , 127 , 130 , 134 , 159 , 165 , 169 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 ]. This will be further discussed in Section 5.5 : Bioinformatics Considerations of Melanoma Diagnosis and Treatment.…”