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 μM activated phosphoinositide 3-kinase (PI3K)/Akt signaling markedly from 12h 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.
Gifu University, Yanagido, Japan. yakao@gifu-u.ac.jp
Yukihiro
Y
Akao
Shunsuke
S
Noguchi
Akio
A
Iio
Keitaro
K
Kojima
Takeshi
T
Takagi
Tomoki
T
Naoe
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D050699:E2F3 Transcription Factor / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics; D014162:Transfection
D000970:Antineoplastic Agents; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005472:Fluorouracil