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Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers

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

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    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
Early online date12 Sep 2016
Publication statusPublished - Jul 2017


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.

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