Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers.
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Date
2016-09-14ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Hepatocytes
Animals
Mice, Knockout
Humans
Carcinoma, Hepatocellular
Cholangiocarcinoma
Bile Duct Neoplasms
Liver Neoplasms
Neoplasms, Experimental
MicroRNAs
RNA, Untranslated
Transfection
Gene Expression Regulation, Neoplastic
Conserved Sequence
beta Catenin
Wnt Signaling Pathway
Research team
Signal Transduction & Molecular Pharmacology
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Language
eng
Date accepted
2016-08-17
License start date
2017-07
Citation
Gut, 2017, 66 (7), pp. 1268 - 1277
Publisher
BMJ PUBLISHING GROUP