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dc.contributor.authorCarotenuto, Pen_US
dc.contributor.authorHedayat, Sen_US
dc.contributor.authorFassan, Men_US
dc.contributor.authorCardinale, Ven_US
dc.contributor.authorLampis, Aen_US
dc.contributor.authorGuzzardo, Ven_US
dc.contributor.authorVicentini, Cen_US
dc.contributor.authorScarpa, Aen_US
dc.contributor.authorCascione, Len_US
dc.contributor.authorCostantini, Den_US
dc.contributor.authorCarpino, Gen_US
dc.contributor.authorAlvaro, Den_US
dc.contributor.authorGhidini, Men_US
dc.contributor.authorTrevisani, Fen_US
dc.contributor.authorTe Poele, Ren_US
dc.contributor.authorSalati, Men_US
dc.contributor.authorVentura, Sen_US
dc.contributor.authorVlachogiannis, Gen_US
dc.contributor.authorHahne, JCen_US
dc.contributor.authorBoulter, Len_US
dc.contributor.authorForbes, SJen_US
dc.contributor.authorGuest, RVen_US
dc.contributor.authorCillo, Uen_US
dc.contributor.authorSaid-Huntingford, Ien_US
dc.contributor.authorBegum, Ren_US
dc.contributor.authorSmyth, Een_US
dc.contributor.authorMichalarea, Ven_US
dc.contributor.authorCunningham, Den_US
dc.contributor.authorRimassa, Len_US
dc.contributor.authorSantoro, Aen_US
dc.contributor.authorRoncalli, Men_US
dc.contributor.authorKirkin, Ven_US
dc.contributor.authorClarke, Pen_US
dc.contributor.authorWorkman, Pen_US
dc.contributor.authorValeri, Nen_US
dc.contributor.authorBraconi, Cen_US
dc.date.accessioned2020-05-12T09:41:45Z
dc.date.issued2020-09-10en_US
dc.identifier.citationHepatology (Baltimore, Md.), 2020, 72 (3), pp. 982 - 996en_US
dc.identifier.issn0270-9139en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3603
dc.identifier.eissn1527-3350en_US
dc.identifier.doi10.1002/hep.31094en_US
dc.description.abstract<h4>Background and aims</h4>Changes in single microRNA (miRNA) expression have been associated with chemo-resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy.<h4>Approach and results</h4>High-throughput screening (HTS) of 997 locked nucleic acid miRNA inhibitors was performed in six cholangiocarcinoma cell lines treated with cisplatin and gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with mirVana probes. MicroRNA and gene expression was assessed by TaqMan assay, RNA-sequencing, and in situ hybridization in four independent cohorts of human BTCs. Knockout of microRNA was achieved by CRISPR-CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in vitro and in vivo. HTS revealed that MIR1249 inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTCs. In validation experiments, MIR1249 inhibition did not alter cell viability in untreated or dimethyl sulfoxide-treated cells; however, it did increase the CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem cell niche of human BTCs as well as in CD133+ chemo-resistant CCLP cells. MIR1249 modulated the chemotherapy-induced enrichment of CD133+ cells by controlling their clonal expansion through the Wnt-regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of cancer stem cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumor shrinkage after exposure to weekly CG, whereas wild-type models showed only stable disease over treatment.<h4>Conclusions</h4>MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics.en_US
dc.formatPrint-Electronicen_US
dc.format.extent982 - 996en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleModulation of Biliary Cancer Chemo-Resistance Through MicroRNA-Mediated Rewiring of the Expansion of CD133+ Cells.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-12-15en_US
rioxxterms.versionofrecord10.1002/hep.31094en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2020-09-10en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfHepatology (Baltimore, Md.)en_US
pubs.issue3en_US
pubs.notesNot knownen_US
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
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/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.publication-statusPublisheden_US
pubs.volume72en_US
pubs.embargo.termsNot knownen_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamEvolutionary Genomics & Modellingen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
dc.contributor.icrauthorHedayat-Husseyin, Somaiehen_US
dc.contributor.icrauthorClarke, Paulen_US
dc.contributor.icrauthorWorkman, Paulen_US
dc.contributor.icrauthorCunningham, Daviden_US
dc.contributor.icrauthorValeri, Nicolaen_US
dc.contributor.icrauthorHahne, Jensen_US
dc.contributor.icrauthorLampis, Andreaen_US


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