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Association among Vitamin D, Retinoic Acid-Related Orphan Receptors, and Vitamin D Hydroxyderivatives in Ovarian
Anna A Brożyna1, Tae-Kang Kim2, Marzena Zabłocka3
1Department of Human Biology, Institute of Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Toruń, Poland.
Abstract:
Vitamin D and its derivatives, acting via the vitamin D receptor (VDR) and retinoic acid-related orphan receptors γ and α (RORγ and RORα), show anticancer properties. Since pathological conditions are characterized by disturbances in the expression of these receptors, in this study, we investigated their expression in ovarian cancers (OCs), as well as explored the phenotypic effects of vitamin D hydroxyderivatives and RORγ/α agonists on OC cells. The VDR and RORγ showed both a nuclear and a cytoplasmic location, and their expression levels were found to be reduced in the primary and metastatic OCs in comparison to normal ovarian epithelium, as well as correlated to the tumor grade. This reduction in VDR and RORγ expression correlated with a shorter overall disease-free survival. VDR, RORγ, and RORα were also detected in SKOV-3 and OVCAR-3 cell lines with increased expression in the latter line. 20-Hydroxy-lumisterol3 (20(OH)L3) and synthetic RORα/RORγ agonist SR1078 inhibited proliferation only in the OVCAR-3 line, while 20-hydroxyvitamin-D3 (20(OH)D3) only inhibited SKOV-3 cell proliferation. 1,25(OH)2D3, 20(OH)L3, and SR1078, but not 20(OH)D3, inhibited spheroid formation in SKOV-3 cells. In summary, decreases in VDR, RORγ, and RORα expression correlated with an unfavorable outcome for OC, and compounds targeting these receptors had a context-dependent anti-tumor activity in vitro. We conclude that VDR and RORγ expression can be used in the diagnosis and prognosis of OC and suggest their ligands as potential candidates for OC therapy.
Insights
Reduced vitamin D receptor (VDR) and RORγ expression in ovarian cancer correlates with poor prognosis. Targeting these receptors with specific compounds shows potential for ovarian cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Vitamin D receptor (VDR) and retinoic acid-related orphan receptors (RORs) are implicated in anticancer mechanisms.
- Disturbances in VDR and ROR expression are observed in pathological conditions.
- Ovarian cancer (OC) is a significant health concern with a need for improved therapeutic strategies.
Purpose of the Study:
- To investigate the expression of VDR, RORγ, and RORα in ovarian cancers.
- To explore the effects of vitamin D derivatives and ROR agonists on OC cells.
- To assess the prognostic value of VDR and ROR expression in OC.
Main Methods:
- Immunohistochemical analysis of VDR and RORγ expression in primary and metastatic OCs and normal ovarian epithelium.
- Detection of VDR, RORγ, and RORα in OC cell lines (SKOV-3, OVCAR-3).
- In vitro treatment of OC cells with vitamin D hydroxyderivatives (20(OH)D3, 1,25(OH)2D3, 20(OH)L3) and RORα/RORγ agonist (SR1078) to assess proliferation and spheroid formation.
Main Results:
- VDR and RORγ expression were reduced in primary and metastatic OCs compared to normal tissue and correlated with tumor grade.
- Lower VDR and RORγ expression correlated with shorter disease-free survival.
- Vitamin D derivatives and ROR agonists demonstrated context-dependent inhibition of proliferation and spheroid formation in OC cell lines.
Conclusions:
- Decreased VDR, RORγ, and RORα expression is associated with unfavorable outcomes in ovarian cancer.
- VDR and RORγ expression levels may serve as diagnostic and prognostic markers for OC.
- Ligands targeting VDR and RORs represent potential therapeutic candidates for ovarian cancer treatment.
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