MicroRNA regulates human vitamin D receptor

Abstract

Most of the biological effects of 1α,25-dihydroxyvitamin D 3 (1,25(OH)2D3) 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. Micro-RNAs (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 30-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)2D3 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)2D3 in MCF-7 cells were significantly abolished by the overexpression of miR-125b. These results suggest that the endogenous VDR level was repressed by miR-125b. 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)2D3. © 2009 UICC.