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Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

Carotenuto, Pietro, Fassan, Matteo, Pandolfo, Rosantony, Lampis, Andrea, Vicentini, Caterina, Cascione, Luciano, Paulus-Hock, Viola, Boulter, Luke, Guest, Rachel, Quagliata, Luca, Hahne, Jens Claus, Ridgway, Rachel, Jamieson, Tam, Athineos, Dimitris, Veronese, Angelo, Visone, Rosa, Murgia, Claudio, Ferrari, Giulia, Guzzardo, Vincenza, Evans, Thomas Ronald Jeffry, MacLeod, Martin, Feng, Gui Ji, Dale, Trevor Clive, Negrini, Massimo, Forbes, Stuart J, Terracciano, Luigi, Scarpa, Aldo, Patel, Tushar, Valeri, Nicola, Workman, Paul, Sansom, Owen and Braconi, Chiara 2017. Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut 66 (7) , pp. 1268-1277. 10.1136/gutjnl-2016-312278

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Abstract

Objective Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/β-catenin pathway in liver cancer. Design Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/β-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation. Results Overexpression of the T-UCR uc.158− could differentiate Wnt/β-catenin dependent HCC from normal liver and from β-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158− was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of β-catenin altered uc.158− expression in human malignant hepatocytes. uc.158− expression was increased in CTNNB1-mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of β-catenin. uc.158− was increased in TAA rat CCA and reduced after treatment with Wnt/β-catenin inhibitors. uc.158− expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158− reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158− sequence. Modulation of uc.158− changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158− inhibitor and anti-miR-193b rescued the effect of uc.158− inhibition on cell viability. Conclusions We showed that uc.158− is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: BMJ Publishing Group Ltd
ISSN: 0017-5749
Date of First Compliant Deposit: 7 October 2016
Date of Acceptance: 17 August 2016
Last Modified: 25 Jul 2019 22:41
URI: http://orca.cf.ac.uk/id/eprint/95129

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