Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers.

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ICR Authors

Carotenuto, Pietro
 Lampis, Andrea
 Hahne, Jens
 Valeri, Nicola
 Workman, Paul
 Braconi, Chiara

Authors

Carotenuto, P
Fassan, M
Pandolfo, R
Lampis, A
Vicentini, C
Cascione, L
Paulus-Hock, V
Boulter, L
Guest, R
Quagliata, L
Hahne, JC
Ridgway, R
Jamieson, T
Athineos, D
Veronese, A
Visone, R
Murgia, C
Ferrari, G
Guzzardo, V
Evans, TRJ
MacLeod, M
Feng, GJ
Dale, T
Negrini, M
Forbes, SJ
Terracciano, L
Scarpa, A
Patel, T
Valeri, N
Workman, P
Sansom, O
Braconi, C

Document Type

Journal Article

Date

2016-09-14

Date Accepted

2016-08-17

Date Available

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.

Citation

Gut, 2017, 66 (7), pp. 1268 - 1277

DOI

10.1136/gutjnl-2016-312278

URI

https://repository.icr.ac.uk/handle/internal/131

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

BMJ PUBLISHING GROUP

ISSN

0017-5749

eISSN

1468-3288

Collections

Cancer Therapeutics
Molecular Pathology

Research Team

Signal Transduction & Molecular Pharmacology
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics

Notes