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Mutated beta-catenin evades a microRNA-dependent regulatory loop.

ABSTRACT: hsa-mir-483 is located within intron 2 of the IGF2 gene. We have previously shown oncogenic features of miR-483-3p through cooperation with IGF2 or by independently targeting the proapoptotic gene BBC3/PUMA. Here we demonstrate that expression of miR-483 can be induced independently of IGF2 by the oncoprotein ?-catenin through an interaction with the basic helix-loop-helix protein upstream stimulatory transcription factor 1. We also show that ?-catenin itself is a target of miR-483-3p, triggering a negative regulatory loop that becomes ineffective in cells harboring an activating mutation of ?-catenin. These results provide insights into the complex regulation of the IGF2/miR-483 locus, revealing players in the ?-catenin pathway.

SUBMITTER: Veronese A

PROVIDER: S-EPMC3064338 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Mutated beta-catenin evades a microRNA-dependent regulatory loop.

Veronese Angelo A Visone Rosa R Consiglio Jessica J Acunzo Mario M Lupini Laura L Kim Taewan T Ferracin Manuela M Lovat Francesca F Miotto Elena E Balatti Veronica V D'Abundo Lucilla L Gramantieri Laura L Bolondi Luigi L Pekarsky Yuri Y Perrotti Danilo D Negrini Massimo M Croce Carlo M CM

Proceedings of the National Academy of Sciences of the United States of America 20110307 12

hsa-mir-483 is located within intron 2 of the IGF2 gene. We have previously shown oncogenic features of miR-483-3p through cooperation with IGF2 or by independently targeting the proapoptotic gene BBC3/PUMA. Here we demonstrate that expression of miR-483 can be induced independently of IGF2 by the oncoprotein β-catenin through an interaction with the basic helix-loop-helix protein upstream stimulatory transcription factor 1. We also show that β-catenin itself is a target of miR-483-3p, triggerin ...[more]

PMID: 21383185

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Project description:Background & aimsMicroRNAs (miRNAs) have been implicated in the development and progression of human cancers. We investigated the roles and mechanisms of miR-26a in human cholangiocarcinoma.MethodsWe used in situ hybridization and quantitative reverse transcriptase polymerase chain reaction to measure expression of miR-26a in human cholangiocarcinoma tissues and cell lines (eg, CCLP1, SG231, HuCCT1, TFK1). Human cholangiocarcinoma cell lines were transduced with lentiviruses that expressed miR-26a1 or a scrambled sequence (control); proliferation and colony formation were analyzed. We analyzed growth of human cholangiocarcinoma cells that overexpress miR-26a or its inhibitor in severe combined immune-deficient mice. Immunoblot, immunoprecipitation, DNA pull-down, immunofluorescence, and luciferase reporter assays were used to measure expression and activity of glycogen synthase kinase (GSK)-3β, β-catenin, and related signaling molecules.ResultsHuman cholangiocarcinoma tissues and cell lines had increased levels of miR-26a compared with the noncancerous biliary epithelial cells. Overexpression of miR-26a increased proliferation of cholangiocarcinoma cells and colony formation in vitro, whereas miR-26 depletion reduced these parameters. In severe combined immune-deficient mice, overexpression of miR-26a by cholangiocarcinoma cells increased tumor growth and overexpression of the miR-26a inhibitor reduced it. GSK-3β messenger RNA was identified as a direct target of miR-26a by computational analysis and experimental assays. miR-26a-mediated reduction of GSK-3β resulted in activation of β-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator-activated receptor δ. Depletion of β-catenin partially prevented miR-26a-induced tumor cell proliferation and colony formation.ConclusionsmiR-26a promotes cholangiocarcinoma growth by inhibition of GSK-3β and subsequent activation of β-catenin. These signaling molecules might be targets for prevention or treatment of cholangiocarcinoma.

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Mutated beta-catenin evades a microRNA-dependent regulatory loop.

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Mutated beta-catenin evades a microRNA-dependent regulatory loop.

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