MicroRNA regulates human vitamin D receptor

Abstract

Most of the biological effects of 1a, 25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) are elicited by the binding to vitamin D receptor (VDR), which regulates gene expression. Earlier studies reported no correlation between the VDR protein and mRNA levels, suggesting the involvement of posttranscriptional regulation. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression through translational repression or mRNA degradation. A potential miR-125b recognition element (MRE125b) was identified in the 3 0 -untranslated region of human VDR mRNA. We investigated whether VDR is regulated by miR-125b. In luciferase assays using a plasmid containing the MRE125b, the antisense oligonucleotide for miR-125b significantly increased (130% of control) the reporter activity in KGN cells, whereas the precursor for miR-125b significantly decreased (40% of control) the reporter activity in MCF-7 cells, suggesting that miR-125b functionally recognized the MRE125b. By electrophoretic mobility shift assays, it was demonstrated that the overexpression of miR-125b significantly decreased the endogenous VDR protein level in MCF-7 cells to 40% of control. 1,25(OH) 2 D 3 drastically induced the CYP24 mRNA level in MCF-7 cells, but the induction was markedly attenuated by the overexpression of miR-125b. In addition, the antiproliferative effects of 1,25(OH) 2 D 3 in MCF-7 cells were significantly abolished by the overexpression of miR-125b. These results suggest that the endogenous VDR level was repressed by miR125b. In conclusion, we found that miR-125b posttranscriptionally regulated human VDR. Since the miR-125b level is known to be downregulated in cancer, such a decrease may result in the upregulation of VDR in cancer and augmentation of the antitumor effects of 1,25(OH) 2 D 3 .

MicroRNA-125b Confers the Resistance of Breast Cancer Cells to Paclitaxel through Suppression of Pro-apoptotic Bcl-2 Antagonist Killer 1 (Bak1) Expression

“…Two recent studies reported that miR-125b may act as an oncogene in human breast cancer cells. One study reported that miR-125b promoted cell proliferation and decreased the antitumor effects of 1,25(OH)(2)D(3) in breast cancer MCF7 cells (52). Another study showed that compared with nontumorigenic cancer cells, miR-125b is overexpressed in highly tumorigenic human breast cancer stem cells (53).…”

Vitamin D and colon cancer

“…Thus, it has been reported that miR-27b (MIR27B) and miR-298 (MIR298) reduce VDR levels in LS-180 colon cancer cells (Pan et al 2009). In addition, Mohri et al (2009) have shown that miR-125b (MIR125B) down-regulates VDR expression and reduces 1,25(OH) 2 D 3 action in breast cancer cells. Interestingly, miR-125b has been found to be over-expressed in colon cancer metastases (Baffa et al 2009).…”

Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

“…However, the miRNA:mRNA pairs largely remain to be identified. Recently, we reported that miRNAs were involved in the regulation of human xenobiotics-metabolizing enzymes such as CYP1B1 (Tsuchiya et al, 2006) and CYP2E1 (Mohri et al, 2010) and human nuclear receptors such as pregnane X receptor (Takagi et al, 2008), vitamin D receptor (Mohri et al, 2009), and hepatocyte nuclear factor 4α (Takagi et al, 2010). As a sequel study, we focused on human aryl hydrocarbon receptor nuclear translocator (ARNT).…”