期刊
RNA
卷 19, 期 6, 页码 778-788出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.036483.112
关键词
microRNA; post-transcriptional up-regulation; GPC3; ERN1; RIDD; FunREG
资金
- 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
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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