On the relationship between VDR, RORα and RORγ receptors expression and HIF1-α levels in human melanomas.

ABSTRACT

We analysed 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 = -.2273, P = .0302; r = -.5081, P = .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 = .2438, P = .0175; r = .3662, P = .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 = .2743, P = .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 = .3667; P = .0327; r = .4208, P = .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.