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dc.contributor.authorCarotenuto, P
dc.contributor.authorFassan, M
dc.contributor.authorPandolfo, R
dc.contributor.authorLampis, A
dc.contributor.authorVicentini, C
dc.contributor.authorCascione, L
dc.contributor.authorPaulus-Hock, V
dc.contributor.authorBoulter, L
dc.contributor.authorGuest, R
dc.contributor.authorQuagliata, L
dc.contributor.authorHahne, JC
dc.contributor.authorRidgway, R
dc.contributor.authorJamieson, T
dc.contributor.authorAthineos, D
dc.contributor.authorVeronese, A
dc.contributor.authorVisone, R
dc.contributor.authorMurgia, C
dc.contributor.authorFerrari, G
dc.contributor.authorGuzzardo, V
dc.contributor.authorEvans, TRJ
dc.contributor.authorMacLeod, M
dc.contributor.authorFeng, GJ
dc.contributor.authorDale, T
dc.contributor.authorNegrini, M
dc.contributor.authorForbes, SJ
dc.contributor.authorTerracciano, L
dc.contributor.authorScarpa, A
dc.contributor.authorPatel, T
dc.contributor.authorValeri, N
dc.contributor.authorWorkman, P
dc.contributor.authorSansom, O
dc.contributor.authorBraconi, C
dc.date.accessioned2016-09-28T11:20:26Z
dc.date.issued2016-09-14
dc.identifier.citationGut, 2017, 66 (7), pp. 1268 - 1277
dc.identifier.issn0017-5749
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/131
dc.identifier.eissn1468-3288
dc.identifier.doi10.1136/gutjnl-2016-312278
dc.description.abstractOBJECTIVE: 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.
dc.formatPrint-Electronic
dc.format.extent1268 - 1277
dc.languageeng
dc.language.isoeng
dc.publisherBMJ PUBLISHING GROUP
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHepatocytes
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectCarcinoma, Hepatocellular
dc.subjectCholangiocarcinoma
dc.subjectBile Duct Neoplasms
dc.subjectLiver Neoplasms
dc.subjectNeoplasms, Experimental
dc.subjectMicroRNAs
dc.subjectRNA, Untranslated
dc.subjectTransfection
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectConserved Sequence
dc.subjectbeta Catenin
dc.subjectWnt Signaling Pathway
dc.titleWnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers.
dc.typeJournal Article
dcterms.dateAccepted2016-08-17
rioxxterms.versionofrecord10.1136/gutjnl-2016-312278
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGut
pubs.issue7
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.publication-statusPublished
pubs.volume66
pubs.embargo.termsNot known
icr.researchteamSignal Transduction & Molecular Pharmacology
icr.researchteamEvolutionary Genomics & Modelling
icr.researchteamGastrointestinal Cancer Biology and Genomics
dc.contributor.icrauthorCarotenuto, Pietro
dc.contributor.icrauthorLampis, Andrea
dc.contributor.icrauthorHahne, Jens
dc.contributor.icrauthorValeri, Nicola
dc.contributor.icrauthorWorkman, Paul
dc.contributor.icrauthorBraconi, Chiara


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