Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers.
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.



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.



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 inCTNNB1-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.



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.
The Institute of Cancer Research, London, UK.
Pietro
P
Carotenuto
Department of Medicine, University of Padua, Padua, Italy.|ARC-NET Research Centre, University of Verona, Verona, Italy.
Matteo
M
Fassan
The Institute of Cancer Research, London, UK.
Rosantony
R
Pandolfo
The Institute of Cancer Research, London, UK.
Andrea
A
Lampis
ARC-NET Research Centre, University of Verona, Verona, Italy.
Caterina
C
Vicentini
Institute of Oncology Research, Bellinzona, Switzerland.
Luciano
L
Cascione
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Viola
V
Paulus-Hock
MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK.
Luke
L
Boulter
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Rachel
R
Guest
Molecular Pathology Division, Institute of Pathology, University of Basel, Basel, Switzerland.
Luca
L
Quagliata
The Institute of Cancer Research, London, UK.
Jens Claus
JC
Hahne
Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK.
Rachel
R
Ridgway
Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK.
Tam
T
Jamieson
Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK.
Dimitris
D
Athineos
Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
Angelo
A
Veronese
Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
Rosa
R
Visone
Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK.
Claudio
C
Murgia
The Institute of Cancer Research, London, UK.
Giulia
G
Ferrari
Department of Medicine, University of Padua, Padua, Italy.
Vincenza
V
Guzzardo
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Thomas Ronald Jeffry
TRJ
Evans
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Martin
M
MacLeod
School of Biosciences, Cardiff University, Cardiff, UK.
Gui Ji
GJ
Feng
School of Biosciences, Cardiff University, Cardiff, UK.
Trevor
T
Dale
University of Ferrara, Ferrara, Italy.
Massimo
M
Negrini
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Stuart J
SJ
Forbes
Molecular Pathology Division, Institute of Pathology, University of Basel, Basel, Switzerland.
Luigi
L
Terracciano
ARC-NET Research Centre, University of Verona, Verona, Italy.
Aldo
A
Scarpa
Mayo Clinic, Jacksonville, Florida, USA.
Tushar
T
Patel
The Institute of Cancer Research, London, UK.|The Royal Marsden NHS Foundation Trust, London and Surrey, UK.
Nicola
N
Valeri
The Institute of Cancer Research, London, UK.
Paul
P
Workman
Cancer Research UK Beatson Institute for Cancer Research, Glasgow, UK.
Owen
O
Sansom
The Institute of Cancer Research, London, UK.|The Royal Marsden NHS Foundation Trust, London and Surrey, UK.
Chiara
0000-0003-4835-1259
C
Braconi
D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D009374:Neoplasms, Experimental; D022661:RNA, Untranslated / Q000235:genetics*; D014162:Transfection; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D022661:RNA, Untranslated; D051176:beta Catenin
BILARY DUCT CARCINOMA; CHOLANGIOCARCINOMA; HEPATOCELLULAR CARCINOMA; RNA EXPRESSION