title: MicroRNA-1291-mediated silencing of IRE1α 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.
authors.affiliation: Groupe de Recherche sur L’Étude du Foie, Université Bordeaux Segalen, F-33000 Bordeaux, France. m.marionmaurel@gmail.com
authors.forename: Marion
authors.initials: M
authors.lastname: Maurel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dejeans
authors.forename: Saïd
authors.initials: S
authors.lastname: Taouji
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.forename: Christophe F
authors.initials: CF
authors.lastname: Grosset
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059367:RNA Cleavage; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D019076:Transgenes
chemical_list: D020413:3' Untranslated Regions; C105937:GPC3 protein, human; D053673:Glypicans; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: ERN1; FunREG; GPC3; RIDD; microRNA; post-transcriptional up-regulation