Calcitriol increases Dicer expression and modifies the microRNAs signature in SiHa cervical cancer cells

Abstract

MicroRNAs play important roles in cancer biology. Calcitriol, the hormonal form of vitamin D3, regulates microRNAs expression in tumor cells. In the present study we asked if calcitriol would modify some of the components of the microRNA processing machinery, namely, Drosha and Dicer, in calcitriol-responsive cervical cancer cells. We found that calcitriol treatment did not affect Drosha mRNA; however, it significantly increased Dicer mRNA and protein expression in VDR-positive SiHa and HeLa cells. In VDR-negative C33-A cells, calcitriol had no effect on Dicer mRNA. We also found a vitamin D response element in Dicer promoter that interacts in vitro to vitamin D and retinoid X receptors. To explore the biological plausibility of these results, we asked if calcitriol alters the microRNA expression profile in SiHa cells. Our results revealed that calcitriol regulates the expression of a subset of microRNAs with potential regulatory functions in cancer pathways, such as miR-22, miR-296-3p, and miR-498, which exert tumor-suppressive effects. In summary, the data indicate that in SiHa cells, calcitriol stimulates the expression of Dicer possibly through the vitamin D response element located in its promoter. This may explain the calcitriol-dependent modulation of microRNAs whose target mRNAs are related to anticancer pathways, further adding to the various anticancer mechanisms of calcitriol.

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

“…Dicer produces mature miRNAs by promoting miRNA processing. The down-regulation of microRNAs mediating the loss of Dicer expression has been associated with breast cancer progression [18,45]. Iosue et al (2013) reported that calcitriol down-regulated miR-17-5p expression in acute myeloid leukemia cells [46].…”

“…Seuter et al (2013) have demonstrated that calcitriol-induced transcription correlated with the chromatin accessibility of VDR binding regions, and also that calcitriol epigenetically regulated tumor-related VDR target genes through DNA methylation and histone modifications [16,17]. Moreover, calcitriol has been shown to regulate protein degradation through the modulation of proteases and protease inhibitors [10] and specific microRNA (miRNA) processing by enhancing the expression of Dicer in cancer cells [18]. …”

Fine tuning of vitamin D receptor (VDR) activity by post-transcriptional and post-translational modifications

“…Upon binding of VDR/RXR to VDRE, the amount of Dicer was increased on both levels, mRNA and protein. However, upregulation of Dicer was observed only at high concentration of 1,25(OH) 2 D (1 mM) [46]. Among the most affected miRNAs were miR-22 (miR-22 regulates telomerase necessary for many types of cancer), miR-296-3p and miR-498.…”

“…Among the most affected miRNAs were miR-22 (miR-22 regulates telomerase necessary for many types of cancer), miR-296-3p and miR-498. All three miRNAs are involved in anticancer actions and were upregulated [46]. Nevertheless, this finding has probably no serious implication in clinical practice since serum 25(OH)D levels above 150 ng/mL are considered as vitamin D intoxication [47].…”

“…Nevertheless, this finding has probably no serious implication in clinical practice since serum 25(OH)D levels above 150 ng/mL are considered as vitamin D intoxication [47]. Moreover, due to the tight control of 1,25(OH) 2 D formation, serum levels similar to that used in the study mentioned [46] are not reachable.…”