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dc.contributor.authorLampis, A
dc.contributor.authorHahne, JC
dc.contributor.authorGasparini, P
dc.contributor.authorCascione, L
dc.contributor.authorHedayat, S
dc.contributor.authorVlachogiannis, G
dc.contributor.authorMurgia, C
dc.contributor.authorFontana, E
dc.contributor.authorEdwards, J
dc.contributor.authorHorgan, PG
dc.contributor.authorTerracciano, L
dc.contributor.authorSansom, OJ
dc.contributor.authorMartins, CD
dc.contributor.authorKramer-Marek, G
dc.contributor.authorCroce, CM
dc.contributor.authorBraconi, C
dc.contributor.authorFassan, M
dc.contributor.authorValeri, N
dc.date.accessioned2021-07-13T15:19:04Z
dc.date.available2021-07-13T15:19:04Z
dc.date.issued2021-07-05
dc.identifier.citationCell death and differentiation, 2021en_US
dc.identifier.issn1350-9047
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4683
dc.identifier.eissn1476-5403en_US
dc.identifier.eissn1476-5403
dc.identifier.doi10.1038/s41418-021-00820-0en_US
dc.identifier.doi10.1038/s41418-021-00820-0
dc.description.abstractJunctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.en_US
dc.formatPrint-Electronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleMIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2021-06-09
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1038/s41418-021-00820-0en_US
rioxxterms.licenseref.startdate2021-07-05
dc.relation.isPartOfCell death and differentiationen_US
pubs.notesNo embargoen_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/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-statusPublisheden_US
pubs.embargo.termsNo embargoen_US
icr.researchteamEvolutionary Genomics & Modelling
icr.researchteamGastrointestinal Cancer Biology and Genomics
dc.contributor.icrauthorLampis, Andreaen_US
dc.contributor.icrauthorValeri, Nicolaen_US
dc.contributor.icrauthorHahne, Jensen_US


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