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Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism.
- Source :
-
Oncotarget [Oncotarget] 2017 Jul 11; Vol. 8 (28), pp. 46219-46233. - Publication Year :
- 2017
-
Abstract
- 5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the translational machinery and that 5-FU affects the amount of some mRNAs associated with ribosomes. However, the impact of 5-FU on translational regulation remains unclear. Using translatome profiling, we report that a clinically relevant dose of 5-FU induces a translational reprogramming in colorectal cancer cell lines. Comparison of mRNA distribution between polysomal and non-polysomal fractions in response to 5-FU treatment using microarray quantification identified 313 genes whose translation was selectively regulated. These regulations were mostly stimulatory (91%). Among these genes, we showed that 5-FU increases the mRNA translation of HIVEP2, which encodes a transcription factor whose translation in normal condition is known to be inhibited by mir-155. In response to 5-FU, the expression of mir-155 decreases thus stimulating the translation of HIVEP2 mRNA. Interestingly, the 5-FU-induced increase in specific mRNA translation was associated with reduction of global protein synthesis. Altogether, these findings indicate that 5-FU promotes a translational reprogramming leading to the increased translation of a subset of mRNAs that involves at least for some of them, miRNA-dependent mechanisms. This study supports a still poorly evaluated role of translational control in drug response.
- Subjects :
- Cellular Reprogramming
Colonic Neoplasms genetics
Colorectal Neoplasms genetics
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Drug Resistance, Neoplasm
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
HCT116 Cells
HT29 Cells
Humans
Protein Biosynthesis drug effects
Transcription Factors genetics
Transcription Factors metabolism
Colonic Neoplasms therapy
Colorectal Neoplasms therapy
Fluorouracil therapeutic use
MicroRNAs genetics
RNA, Messenger genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28515355
- Full Text :
- https://doi.org/10.18632/oncotarget.17597