Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

Pietro Carotenuto, Matteo Fassan, Rosantony Pandolfo, Andrea Lampis, Caterina Vicentini, Luciano Cascione, Viola Paulus-Hock, Luke Boulter, Rachel Guest, Luca Quagliata, Jens Claus Hahne, Rachel Ridgway, Tam Jamieson, Dimitris Athineos, Angelo Veronese, Rosa Visone, Claudio Murgia, Giulia Ferrari, Vincenza Guzzardo, Thomas Ronald Jeffry EvansMartin MacLeod, Gui Ji Feng, Trevor Dale, Massimo Negrini, Stuart J. Forbes, Luigi Terracciano, Aldo Scarpa, Tushar Patel, Nicola Valeri, Paul Workman, Owen Sansom, Chiara Braconi

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1268-1277
Number of pages10
JournalGut
Volume66
Issue number7
DOIs
StatePublished - Jul 1 2017

Keywords

  • BILARY DUCT CARCINOMA
  • CHOLANGIOCARCINOMA
  • HEPATOCELLULAR CARCINOMA
  • RNA EXPRESSION

ASJC Scopus subject areas

  • Gastroenterology

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