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Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management
Open accessAbstract
Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2 D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2 D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.
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“CYP11A1 initiates novel pathways of vitamin D3 activation in various organs or tissue, such as skin, peripheral tissue, adrenals, placenta, gastrointestinal (GI) tract, and several cancer cells of different origin [23,[27], [28], [29], [30], [31], [32], [33]].”
In the citing paper
“It also inhibits malignant transformation, tumor progression and has anti-cancer properties on a variety of tumors including those of gastrointestinal, genitourinary, breast, prostate and lung origins [32, 33, 46, 51], as well as melanoma [52, 53].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [53]
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Flagged first, then by citations
9 of the 311 references couldn’t be matched to a known paper.
Research works printed but not linked: 4
- Slominski, 2013, Novel vitamin D photoproducts and their precursors in the skin, Dermatoendocrinol, 5, 7, 10.4161/derm.23938 · DOI · Paper page
- Tuckey, 2011, Production of 22-hydroxy-metabolites of vitamin D3 by cytochrome P450scc (CYP11A1) and analysis of their biological activities on skin cells, Drug Metab Dispos, 39, 1577, 10.1124/dmd.111.040071 · DOI · Paper page
- Slominski A, Janjetovic Z, Kim T-K et al, Novel vitamin D hydroxyderivatives inhibit melanoma growth and show differential effects on normal melanocytes. Anticancer Res 2012; 32: 3733–3742.
- Zmijewski, 2008, Synthesis and photo-conversion of androsta- and pregna-5,7-dienes to vitamin D3-like derivatives, Photochem Photobiol Sci, 7, 1570, 10.1039/b809005j · DOI · Paper page
Cited by
Sorted by citations
Exploring vitamin D metabolism and function in cancer
Jeon, S., & Shin, E. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0038-9 · Cited by 576
An Update on Vitamin D Metabolism
Saponaro, F., Saba, A., & Zucchi, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186573 · Cited by 339
Melanoma, Melanin, and Melanogenesis: The Yin and Yang Relationship
Slominski, R. M., Sarna, T., Plonka, P. M., Raman, C., Brożyna, A. A., & Slominski, A. T. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.842496 · Cited by 310
Self-citationThe serum vitamin D metabolome: what we know and what is still to discover
Tuckey, R. C., Cheng, C. Y. S., & Slominski, A. T. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2018.09.003 · Cited by 245
Self-citationPhotoprotective Properties of Vitamin D and Lumisterol Hydroxyderivatives
Slominski, A. T., Chaiprasongsuk, A., Janjetović, Z., Kim, T., Stefan, J., Slominski, R. M., Hanumanthu, V. S., Raman, C., Qayyum, S., Song, Y., et al. (2020) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-020-00913-6 · Cited by 151
Self-citation
Metadata
- Authors
- Slominski, A. T., Brożyna, A. A., Zmijewski, M. A., Jóźwicki, W., Jetten, A. M., Mason, R. S., Tuckey, R. C., & Elmets, C. A.
- Affiliations
- University of Alabama at Birmingham (US)
- Nicolaus Copernicus University (PL)
- Gdańsk Medical University (PL)
- National Institutes of Health (US)
- The University of Sydney (AU)
- The University of Western Australia (AU)
- Corresponding author
- Slominski, Andrzej T
- ORCID
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 97
- Issue
- 6
- Pages
- 706-724
- ISSN
- 0023-6837 (ISSN-L)
- PMC
- PMC5446295
- OpenAlex
- W2589902824
- Cited by
- 136
- References
- 311
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 13 · 2023: 14 · 2022: 18 · 2021: 15 · 2020: 24 · 2019: 16 · 2018: 12 · 2017: 8
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX003395)
- Narodowym Centrum Nauki
- National Institutes of Health (Z01-ES-101586)
- National Health and Medical Research Council (1070688)
- National Cancer Institute (R01CA193885)
- National Institute of Environmental Health Sciences (Z01ES101586)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR066505, R01AR052190, R01AR056666)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Keywords
- vitamin D signaling, melanoma, vitamin D receptor, vitamin D binding protein, CYP27B1, CYP24A1, CYP27A1, CYP2R1, CYP11A1, 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D, UV-B radiation, melanoma progression, survival outcomes, single nucleotide polymorphisms, photoprotection
- MeSH terms
- Animals, Cytochrome P-450 Enzyme System, Epidermis, Humans, Melanoma, Ultraviolet Rays, Vitamin D, Signal Transduction, Receptors, Calcitriol, Disease Progression, Mice
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