Publication date: Jul 09, 2019
We analyzed the correlation between the expression of HIF-1α (hypoxia-inducible factor 1 alpha), the nuclear receptors, VDR (vitamin D receptor), RORα (retinoic acid receptor-related orphan receptor alpha), and RORγ and CYP24A1 (cytochrome P450 family 24 subfamily A member 1) and CYP27B1 (cytochrome P450 family 27 subfamily B member 1), enzymes involved in vitamin D metabolism. In primary and metastatic melanomas, VDR negatively correlated with nuclear HIF-1α expression (r=-0.2273, p=0.0302; r=-0.5081, p=0.0011). Furthermore, the highest HIF-1α expression was observed in pT3-pT4 VDR-negative melanomas. A comparative analysis of immunostained HIF-1α and CYP27B1 and CYP24A1 showed lack of correlation between these parameters both in primary tumors and melanoma metastases. In contrast, RORα expression correlated positively with nuclear HIF-1α expression in primary and metastatic lesions (r=0.2438, p=0.0175; r=0.3662, p=0.0166). Comparable levels of HIF-1α expression pattern was observed in localized and advanced melanomas. RORγ in primary melanomas correlated also positively with nuclear HIF-1α expression (r=0.2743, p=0.0129). HIF-1α expression was the lowest in localized RORγ-negative melanomas. In addition, HIF-1α expression correlated with RORγ-positive lymphocytes in melanoma metastases. We further found that in metastatic lymph nodes FoxP3 immunostaining correlated positively with HIF-1α and RORγ expression in melanoma cells (r=0.3667; p=0.0327; r=0.4208, p=0.0129). In summary, our study indicates that the expression of VDR, RORα and RORγ in melanomas is related to hypoxia and/or HIF1-α activity, which also affects FoxP3 expression in metastatic melanoma. Therefore, the hypoxia can affect tumor biology by changing nuclear receptors expression and molecular pathways regulated by nuclear receptors and immune responses. This article is protected by copyright. All rights reserved.
|pathway||BSID||Vitamin D Metabolism|
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