MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review.Vitamin D deficiency is associated with the high risk of colon cancer and a variety of other diseases. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates gene transcription via its nuclear receptor (VDR), and posttranscriptional regulatory mechanisms of gene expression have also been proposed. We have identified microRNA-22 (miR-22) and several other miRNA species as 1,25(OH)2D3 targets in human colon cancer cells. Remarkably, miR-22 is induced by 1,25(OH)2D3 in a time-, dose- and VDR-dependent manner. In SW480-ADH and HCT116 cells, miR-22 loss-of-function by transfection of a miR-22 inhibitor suppresses the antiproliferative effect of 1,25(OH)2D3. Additionally, miR-22 inhibition increases cell migration per se and decreases the antimigratory effect of 1,25(OH)2D3 in both cell types. In silico analysis shows a significant overlap between genes suppressed by 1,25(OH)2D3 and miR-22 putative target genes. Consistently, miR-22 inhibition abrogates the 1,25(OH)2D3-mediated suppression of NELL2, OGN, HNRPH1, RERE and NFAT5 genes. In 39 out of 50 (78%) human colon cancer patients, miR-22 expression was found lower in the tumour than in the matched normal tissue and correlated directly with that of VDR. Our results indicate that miR-22 is induced by 1,25(OH)2D3 in human colon cancer cells and it may contribute to its antitumour action against this neoplasia.This work was supported by the Ministerio de Ciencia e Innovación of Spain (SAF2010-18302), Comunidad de Madrid (Colomics2, S2011/BMD-2344) and Fondo Europeo de Desarrollo Regional-Instituto de Salud Carlos III (RD06/0020/0009 to A.M. and RD06/0020/0020 to F.B.).Peer reviewe