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Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism.

Zeina Bash-Imam, Gabriel Therizols, Anne Vincent, Florian Laforets, Micaela Polay Espinoza, Nathalie Pion, Francoise Macari, Julie Pannequin, Alexandre David, Jean-Christophe Saurin, Hichem C Mertani, Julien Textoris, Didier Auboeuf, Frederic Catez, Nicole Dalla Venezia, Martin Dutertre, Virginie Marcel, and Jean-Jacques Diaz (2017)

Oncotarget, 8(28):46219-46233.

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 reportthat a clinically relevant dose of 5-FU induces a translational reprogramming incolorectal 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 specificmRNA 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.

 
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