Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

Carotenuto, P. et al. (2016) Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut, 66(7), pp. 1268-1277. (doi: 10.1136/gutjnl-2016-312278) (PMID:27618837) (PMCID:PMC5530482)

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: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Braconi, Professor Chiara and MacLeod, Mr Martin and Ridgway, Dr Rachel and Valeri, Dr Nicola and Evans, Professor Jeff and Athineos, Mr Dimitris and Paulus-Hock, Mrs Viola and Murgia, Dr Claudio and Sansom, Professor Owen
• Authors: Carotenuto, P., Fassan, M., Pandolfo, R., Lampis, A., Vicentini, C., Cascione, L., Paulus-Hock, V., Boulter, L., Guest, R., Quagliata, L., Hahne, J. C., Ridgway, R., Jamieson, T., Athineos, D., Veronese, A., Visone, R., Murgia, C., Ferrari, G., Guzzardo, V., Evans, T. R. J., MacLeod, M., Feng, G. J., Dale, T., Negrini, M., Forbes, S. J., Terracciano, L., Scarpa, A., Patel, T., Valeri, N., Workman, P., Sansom, O., and Braconi, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Gut
• Publisher: BMJ Publishing Group
• ISSN: 0017-5749
• ISSN (Online): 1468-3288
• Published Online: 12 September 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Gut 66(7):1268-1277
• Publisher Policy: Reproduced under a Creative Commons License