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Expression of the vitamin D-activating enzyme 1?-hydroxylase (CYP27B1) decreases during melanoma progression.

ABSTRACT: 1?-Hydroxylase (CYP27B1), the enzyme responsible for the synthesis of the biologically active form of vitamin D (1,25(OH)(2)D(3)), is expressed in the skin. To assess the correlation between progression of melanocytic tumors and CYP27B1, we analyzed its expression in 29 benign nevi, 75 primary cutaneous melanomas, 40 metastases, and 4 re-excision and 6 normal skin biopsies. Immunoreactivity for CYP27B1 was significantly lower in the vertical growth phase and metastatic melanomas (0.6 and 0.5 arbitrary units, respectively) in comparison with nevi and radial growth phase tumors (1.2 and 1.1 arbitrary units, respectively); and expression was reduced in more advanced lesions (Clark levels III-V, Breslow thickness ?2.1 mm; 0.8 and 0.7 arbitrary units, respectively). There was an inverse correlation between CYP27B1 and Ki-67 expression. Furthermore, CYP27B1 expression was reduced in primary melanomas that created metastases in comparison with non-metastasizing melanomas. Reduced CYP27B1 expression in radial growth phase was related to shorter overall survival (810 versus 982 versus 1151 days in melanomas with absent, low, and high CYP27B1 immunoreactivity), and low CYP27B1 expression in radial growth phase and vertical growth phase was related to shorter disease-free survival (114 versus 339 versus 737 days and 129 versus 307 versus 737 days, respectively, in melanomas with absent, low, and high CYP27B1). Also, CYP27B1 expression was inversely related to melanin in melanoma cells in vivo and melanoma cells cultured in vitro. Thus, reduction of CYP27B1 correlates with melanoma phenotype and behavior, and its lack affects the survival of melanoma patients, indicating a role in the pathogenesis and progression of this cancer.

SUBMITTER: Brozyna AA

PROVIDER: S-EPMC3529817 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Expression of the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1) decreases during melanoma progression.

Brożyna Anna A AA Jóźwicki Wojciech W Janjetovic Zorica Z Slominski Andrzej T AT

Human pathology 20120917 3

1α-Hydroxylase (CYP27B1), the enzyme responsible for the synthesis of the biologically active form of vitamin D (1,25(OH)(2)D(3)), is expressed in the skin. To assess the correlation between progression of melanocytic tumors and CYP27B1, we analyzed its expression in 29 benign nevi, 75 primary cutaneous melanomas, 40 metastases, and 4 re-excision and 6 normal skin biopsies. Immunoreactivity for CYP27B1 was significantly lower in the vertical growth phase and metastatic melanomas (0.6 and 0.5 arb ...[more]

PMID: 22995334

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Project description:1,25-dihydroxyvitamin D3 affects proliferation, differentiation, and apoptosis and protects DNA against oxidative damage with a net tumorostatic and anticarcinogenic effect. It acts through a specific nuclear receptor that is widely distributed through the body. Although a beneficial role of vitamin D in melanoma patients has been suggested, there is lack of information on the changes in the expression pattern of vitamin D receptor during progression of pigmented lesions. Using immunohistochemistry, we analyzed the expression of vitamin D receptor in 140 samples obtained form 82 patients, including 25 benign nevi, 70 primary cutaneous melanomas, 35 metastases, 5 re-excisions, and 5 normal skin biopsies. The strongest expression was observed in normal skin that significantly decreased in melanocytic proliferations with the following order of expression: normal skin > melanocytic nevi > melanomas = metastases. The vitamin D receptor expression in skin surrounding nevi and melanoma was also significantly reduced as compared to normal skin. Tumor-infiltrating and lymph node lymphocytes retained high levels of vitamin D receptor. There was negative correlation between tumor progression and vitamin D receptor expression with a remarkable decrease of the immunoreactivity in nuclei of melanoma cells at vertical versus radial growth phases and with metastatic melanomas showing the lowest cytoplasmic receptor staining. Furthermore, lack of the receptor expression in primary melanomas and metastases was related to shorter overall patients' survival. In addition, the receptor expression decreased in melanized melanoma cells in comparison to amelanotic or poorly pigmented cells. Therefore, we propose that reduction or absence of vitamin D receptor is linked to progression of melanocytic lesions, that its lack affects survival of melanoma patients, and that melanogenesis can attenuate receptor expression. In conclusion, changes in vitamin D receptor expression pattern can serve as important variables for diagnosis, predicting clinical outcome of the disease, and/or as a guidance for novel therapy of melanomas based on use of vitamin D or its derivatives.

Project description: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)2D3, 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)2D3, 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.

Project description:Objectives:The objective of the present study was to evaluate the pattern of genetic expression of vitamin D receptor (VDR), 1 alpha-hydroxylase (1?-OHase) enzyme and chemokine regulated on activation normal T-cell expressed and secreted (RANTES) in peripheral blood of Holstein dairy cows during transition period. Methods:Blood samples were collected from 16 Holstein dairy cows at 3 weeks prior expected date of delivery (EDD), at the day of parturition, and 3 weeks post-partum for assessment of expression profile of studied genes using real-time PCR and measurement of glucose, ionized calcium (Ca), parathyroid hormone (PTH), inorganic phosphorous (P), sodium (Na), potassium (K), chloride (Cl), and magnesium (Mg) levels. Results:Compared with 3 weeks prior EDD, VDR gene expression decreased significantly at the day of parturition then increased significantly at 3 weeks post-partum. The genetic expression of 1?-OHase enzyme as well as PTH, K, Na and Cl levels increased significantly at the day of parturition. The Ca level decreased significantly at the day of parturition then increased significantly at 3 weeks post-partum. The P level increased significantly at the day of parturition then decreased significantly at 3 weeks post-partum. Glucose level decreased significantly at the day of parturition and at 3 weeks post-partum. RANTES gene expression showed non-significant changes among the three different time points. The expression of VDR gene had a negative correlation with the expression of 1?-OHase enzyme gene, and serum levels of glucose, PTH, P and K, but had a positive correlation with the serum Ca level. The expression of 1?-OHase enzyme gene had a positive correlation with serum levels of PTH, P and K, but had a negative correlation with the serum Ca level. Conclusions:Results of the current study indicate the importance of monitoring the genetic expression of VDR and 1?-OHase enzyme as indicators of metabolic changes during transition period, suggesting that they are candidate genes to judge the health status of dairy cows during such period.

Dataset Information

Expression of the vitamin D-activating enzyme 1?-hydroxylase (CYP27B1) decreases during melanoma progression.

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Expression of the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1) decreases during melanoma progression.

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