Journal
GUT
Volume 66, Issue 7, Pages 1268-1277Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2016-312278
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Funding
- Scottish Senior Clinical Fellowship
- Chief Scientific Office grant from the Scottish Ministry
- Institute of Cancer Research-Clinician Scientist Fellowship
- Marie Curie Career Integration Grant from the European Union
- Research Innovation Fund from Pancreatic Cancer UK
- NIHR Royal Marsden/ICR Biomedical Research Centre project grant
- Cancer Research UK Career Development Award [A18052]
- NIHR Royal Marsden/ICR Biomedical Research Centre Flagship grant
- CR-UK grant [C368/A5140, CRUK A12481, A17196]
- Glasgow Experimental Cancer Medicine Centre grant from Cancer Research UK
- Chief Scientist's Office, Scotland
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [12182]
- European Community FP7 Grant Cam-Pac [602783]
- FIMP, Ministero Salute [CUP_J33G13000210001]
- Medical Research Council
- Cancer Research UK [12946, 18052, 11650, 14889, 11566, 22311, 22897] Funding Source: researchfish
- Pancreatic Cancer UK [RIF2014_01_Braconi] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [21139, 20409] Funding Source: researchfish
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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/beta-catenin pathway in liver cancer. Design Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/beta-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/beta-catenin dependent HCC from normal liver and from beta-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 beta-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 beta-catenin. uc. 158-was increased in TAA rat CCA and reduced after treatment with Wnt/beta-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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