Journal
RNA
Volume 19, Issue 6, Pages 778-788Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.036483.112
Keywords
microRNA; post-transcriptional up-regulation; GPC3; ERN1; RIDD; FunREG
Categories
Funding
- L'Institut National du Cancer (INCa) [INCa_5828]
- La Ligue Nationale contre le Cancer (LNCC)
- INSERM, INCa [INCa_5869, INCa_2012_117]
- Interface contract INSERM-CHU de Bordeaux
- French Research Ministry
- Fondation de France
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MicroRNAs (miRNA) are generally described as negative regulators of gene expression. However, some evidence suggests that they may also play positive roles. As such, we reported that miR-1291 leads to a GPC3 mRNA expression increase in hepatoma cells through a 3' untranslated region (UTR)-dependent mechanism. In the absence of any direct interaction between miR-1291 and GPC3 mRNA, we hypothesized that miR-1291 could act by silencing a negative regulator of GPC3 mRNA expression. Based on in silico predictions and experimental validation, we demonstrate herein that miR-1291 represses the expression of the mRNA encoding the endoplasmic reticulum (ER)-resident stress sensor IRE1 alpha by interacting with a specific site located in the 5' UTR. Moreover, we show, in vitro and in cultured cells, that IRE1 alpha cleaves GPC3 mRNA at a 3' UTR consensus site independently of ER stress, thereby prompting GPC3 mRNA degradation. Finally, we show that the expression of a miR-1291-resistant form of IRE1 alpha abrogates the positive effects of miR-1291 on GPC3 mRNA expression. Collectively, our data demonstrate that miR-1291 is a biologically relevant regulator of GPC3 expression in hepatoma cells and acts through silencing of the ER stress sensor IRE1 alpha.
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