Show simple item record

dc.contributor.authorCarotenuto, P
dc.contributor.authorHedayat, S
dc.contributor.authorFassan, M
dc.contributor.authorCardinale, V
dc.contributor.authorLampis, A
dc.contributor.authorGuzzardo, V
dc.contributor.authorVicentini, C
dc.contributor.authorScarpa, A
dc.contributor.authorCascione, L
dc.contributor.authorCostantini, D
dc.contributor.authorCarpino, G
dc.contributor.authorAlvaro, D
dc.contributor.authorGhidini, M
dc.contributor.authorTrevisani, F
dc.contributor.authorTe Poele, R
dc.contributor.authorSalati, M
dc.contributor.authorVentura, S
dc.contributor.authorVlachogiannis, G
dc.contributor.authorHahne, JC
dc.contributor.authorBoulter, L
dc.contributor.authorForbes, SJ
dc.contributor.authorGuest, RV
dc.contributor.authorCillo, U
dc.contributor.authorSaid-Huntingford, I
dc.contributor.authorBegum, R
dc.contributor.authorSmyth, E
dc.contributor.authorMichalarea, V
dc.contributor.authorCunningham, D
dc.contributor.authorRimassa, L
dc.contributor.authorSantoro, A
dc.contributor.authorRoncalli, M
dc.contributor.authorKirkin, V
dc.contributor.authorClarke, P
dc.contributor.authorWorkman, P
dc.contributor.authorValeri, N
dc.contributor.authorBraconi, C
dc.date.accessioned2020-05-12T09:41:45Z
dc.date.issued2020-09-10
dc.identifier.citationHepatology (Baltimore, Md.), 2020, 72 (3), pp. 982 - 996
dc.identifier.issn0270-9139
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3603
dc.identifier.eissn1527-3350
dc.identifier.doi10.1002/hep.31094
dc.description.abstractBackground and aims 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.Approach and results 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.Conclusions MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics.
dc.formatPrint-Electronic
dc.format.extent982 - 996
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleModulation of Biliary Cancer Chemo-Resistance Through MicroRNA-Mediated Rewiring of the Expansion of CD133+ Cells.
dc.typeJournal Article
dcterms.dateAccepted2019-12-15
rioxxterms.versionofrecord10.1002/hep.31094
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-09-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfHepatology (Baltimore, Md.)
pubs.issue3
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/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.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-statusPublished
pubs.volume72
pubs.embargo.termsNot known
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
dc.contributor.icrauthorHahne, Jensen
dc.contributor.icrauthorLampis, Andreaen
dc.contributor.icrauthorClarke, Paulen
dc.contributor.icrauthorWorkman, Paulen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorValeri, Nicolaen


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0