Downregulation of CYP27A1 Expression and Activity in Human Endometrial Carcinoma Implicates an Abnormal Bioactivation of Vitamin D in Advanced Endometrial Carcinogenesis
Judit Pallares, Laura Bergada, Maria Santacana, Xavier Dolcet, Joan Valls, Adriana Dusso, Xavier Matias-Guiu. Hospital Universitari Arnau de Vilanova , University of Lleida, Irblleida, Lleida, Spain
Background: The association between vitamin D insufficiency and a higher risk to develop several types of human carcinomas has been attributed to an impaired production of 1,25-dihydroxyvitamin D, the vitamin D hormone, from its precursor 25-hydroxyvitamin D and reduced vitamin D receptor (VDR) levels in highly proliferating cells. This study examined whether impaired local bioactivation of vitamin D to 25-hidroxyvitamin D by CYP27A1 contributes to endometrial cell carcinogenesis.
Design: The immunohistochemical expression of CYP27A1, the Vitamin D receptor (VDR), and 24-hydroxylase (CYP24, the enzyme that degrades vitamin D metabolites) was examined in tissue microarrays (TMA) from 80 samples of normal endometrium, and 157 endometrial carcinomas (ECs) with different histological types, FIGO grades, and pathological stages. Three EC cell lines (IK, RL95, HEC1A) were incubated with vitamine D3, and subjected to clonogenic assays.
Results: In normal endometrium (NE), average CYP27A1 and VDR expression levels were lower in the proliferative phase compared to the secretory phase (p=0.06 and p< 0.000, respectively). Interestingly, CYP27A1 expression was significantly higher in EC than in normal endometrium (p = 0.0002) suggesting an attempt by EC cells to compensate for the marked reductions in average VDR levels (EC: 90.7 vs. NE: 142.5; p = 0.0002). In fact, the functional relevance of local vitamin D activation by CYP27A1 in the control of cell carcinogenesis was demonstrated by a dose dependent reduction in the number of EC colonies formed upon a 48 h exposure of the human EC cell lines IK, RL95 and HEC1A to vitamin D3. Furthermore, CYP27A1 was significantly decreased in FIGO grade III tumors (p = 0.072) and stage III carcinomas (p = 0.003). The expected reductions in the levels of CYP24 in parallel with those of VDR expression rule out a role for enhanced catabolism of vitamin D metabolites in EC carcinogenesis in vitamin D deficient states.
Conclusions: Defective local bioactivation of vitamin D, due to vitamin D deficiency or reduced CYP27A1 expression, contributes to endometrial cell carcinogenesis through an impaired control of cell proliferation.
Category: Gynecologic & Obstetrics
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 144, Wednesday Morning