Association among Vitamin D, Retinoic Acid-Related Orphan Receptors, and Vitamin D Hydroxyderivatives in Ovarian Cancer.

Anna A Brożyna,Wojciech Jóźwicki,Junming Yue,Marzena Zabłocka,Tae-Kang Kim,Andrzej T Slominski,Robert C Tuckey,Anton M Jetten

doi:10.3390/nu12113541

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.

Highlights

Ovarian cancer (OC) is the seventh most frequent cancer in women and the leading cause of death in patients with gynecological cancer, with a higher incidence rate and poorer prognosis in less developed counties [1,2]
We reported that RORα and RORγ are expressed in normal human skin and melanomas and that their expression decreases during the progression of melanocytic tumors [48,52]
For the ovarian cancer patient population included in this study, we analyzed 12 cases of matched pairs of primary and metastatic cancers, but no statistically significant differences were found

Summary

Introduction

Ovarian cancer (OC) is the seventh most frequent cancer in women and the leading cause of death in patients with gynecological cancer, with a higher incidence rate and poorer prognosis in less developed counties [1,2]. The 5 year relative survival rate for invasive epithelial ovarian cancer patients is about 45% for all stages [1,2]. OC is sensitive to current treatment regimens (5 year relative survival rate for stage I is 90%). Despite the improvement in treatment, OC patients develop recurrent disease very often, with an overall recurrence rate of 75%, up to 10–30% at early stages [3,4,5]. The 5 year relative survival rate has slightly improved, especially for Caucasians, high recurrence and mortality rates indicate the clear need for developing new methods for early diagnosis, recurrence prediction, and an efficient adjuvant treatment of OC

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Results

Conclusion