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MicroRNA-1291-mediated silencing of IRE1 enhances Glypican-3 expression

Abstract : 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 IRE1α by interacting with a specific site located in the 5' UTR. Moreover, we show, in vitro and in cultured cells, that IRE1α 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 IRE1α 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 IRE1α.
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https://www.hal.inserm.fr/inserm-02437937
Contributor : Christophe Grosset <>
Submitted on : Tuesday, January 14, 2020 - 8:46:18 AM
Last modification on : Wednesday, August 19, 2020 - 10:32:03 AM
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Marion Maurel, Nicolas Dejeans, Saïd Taouji, Eric Chevet, Christophe Grosset. MicroRNA-1291-mediated silencing of IRE1 enhances Glypican-3 expression. RNA, Cold Spring Harbor Laboratory Press, 2013, 19 (6), pp.778-788. ⟨10.1261/rna.036483.112⟩. ⟨inserm-02437937⟩

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