Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells

MiR-34a was identified as one of the down-regulated micro-RNAs (miRs) in human colorectal cancer 5-fluorouracil (5-FU)-resistant DLD-1 cells compared with those in the parental DLD-1 cells Exposure to 5-FU at 30 mu M activated phosphoinositide 3-kinase (PI3K)/Akt signaling markedly from 12 h up to 48 h in the 5-FU-resistant cells compared with that in the parental cells and resulted in an overt difference in growth at those times Furthermore the expression of miR-34a in the 5-FU-resistant cells was, sustained at a low-level whereas it was up-regulated in the parental cells after the 5-FU treatment Sirt1 which is one of the target genes for miR-34a and related to drug-resistance was strikingly up-regulated in the 5-FU-resistant cells The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth as in the parental cells and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3 Moreover the silencing of Sirt1 significantly canceled the resistance to 5-FU in the 5-FU-resistant cells These findings suggest that miR-34a targeting the Sirt1 and E2F3 genes could negatively regulate at least in part the resistance to 5-FU in human colorectal cancer DLD-1 cells (C) 2010 Elsevier Ireland Ltd All rights reserved