dc.contributor.author | Lampis, A | |
dc.contributor.author | Hahne, JC | |
dc.contributor.author | Gasparini, P | |
dc.contributor.author | Cascione, L | |
dc.contributor.author | Hedayat, S | |
dc.contributor.author | Vlachogiannis, G | |
dc.contributor.author | Murgia, C | |
dc.contributor.author | Fontana, E | |
dc.contributor.author | Edwards, J | |
dc.contributor.author | Horgan, PG | |
dc.contributor.author | Terracciano, L | |
dc.contributor.author | Sansom, OJ | |
dc.contributor.author | Martins, CD | |
dc.contributor.author | Kramer-Marek, G | |
dc.contributor.author | Croce, CM | |
dc.contributor.author | Braconi, C | |
dc.contributor.author | Fassan, M | |
dc.contributor.author | Valeri, N | |
dc.date.accessioned | 2021-07-13T15:19:04Z | |
dc.date.available | 2021-07-13T15:19:04Z | |
dc.date.issued | 2021-07-05 | |
dc.identifier.citation | Cell death and differentiation, 2021 | |
dc.identifier.issn | 1350-9047 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4683 | |
dc.identifier.eissn | 1476-5403 | |
dc.identifier.doi | 10.1038/s41418-021-00820-0 | |
dc.description.abstract | Junctional 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. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | SPRINGERNATURE | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-06-09 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41418-021-00820-0 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-07-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cell death and differentiation | |
pubs.notes | No embargo | |
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.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-status | Published | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Evolutionary Genomics & Modelling | |
icr.researchteam | Gastrointestinal Cancer Biology and Genomics | |
icr.researchteam | Evolutionary Genomics & Modelling | |
icr.researchteam | Gastrointestinal Cancer Biology and Genomics | |
dc.contributor.icrauthor | Lampis, Andrea | |
dc.contributor.icrauthor | Hahne, Jens | |
dc.contributor.icrauthor | Hedayat-Husseyin, Somaieh | |
dc.contributor.icrauthor | Kramer-Marek, Gabriela | |
dc.contributor.icrauthor | Valeri, Nicola | |