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Acute endothelial stresses identify microRNA let-7b-5p and non-coding SLC11A2 (NRAMP2/DMT1) exon as biomarkers that overlap with those detected in malignant and non-malignant diseases

2025-09-01Artigo científico Acesso aberto
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dc.contributor.authorBielowka, Adrianna M.
dc.contributor.authorPatel, Dilip
dc.contributor.authorLi, Dongyang
dc.contributor.authorBernabeu-Herrero, Maria E.
dc.contributor.authorGame, Laurence
dc.contributor.authorAldred, Micheala A.
dc.contributor.authorMollet, Inês G.
dc.contributor.authorShovlin, Claire L.
dc.contributor.institutionUCIBIO - Applied Molecular Biosciences Unit
dc.contributor.institutionFaculdade de Ciências e Tecnologia (FCT)
dc.contributor.pblOxford University Press
dc.date.accessioned2026-03-09T11:57:01Z
dc.date.available2026-03-09T11:57:01Z
dc.date.issued2025-09-01
dc.descriptionPublisher Copyright: © 2025 The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians.
dc.description.abstractBackground: Disease biomarkers are often identified long after initiating pathologies, hampering mechanistic understanding and the development of preventative strategies. We hypothesized that aberrant cellular responses to normally-encountered stresses may be relevant to later disease states. Aim: To model two under-explored acute cellular stresses for blood-exposed cells, and cross-reference to known biomarkers of disease. Methods: Normal primary human endothelial cells (ECs) were treated for 1–6h with cycloheximide (CHX) 100μg/ml to inhibit protein translation and nonsense-mediated decay (modelling the integrated stress response), or 10μmol/l ferric citrate (modelling diurnal variation in serum iron that can be augmented by treatments prescribed 8 million times/year in England). Directional whole transcriptome RNA-seq identified differentially expressed genes and micro(mi)RNAs. Customized novel scripts examined the expression of 517 225 exons to predict 1h CHX-stabilized exons. Validations were by cel-miR-39-spiked qRT-PCR and RNA-seq in other EC types, peripheral blood mononuclear cells (PBMCs) and plasma. Results: miRNAs fell transiently at 1h after 10μmol/l ferric citrate (P<0.01), specifically in let-7 family member pre-miRNAs (‘let-7’, P<0.05), where there was an accompanying differential 6h increased expression of 570 let-7-target mRNAs identified through TargetScan (P<0.0001). qRT-PCR and RNA-seq validations in other normal ECs, plasma and PBMCs confirmed up to 80% falls in pre-let-7b/let-7b-5p after 1h iron, and exon 3B of the SLC11A2 (NRAMP2/DMT1)-encoded iron/copper transporter as a novel exon most consistently stabilized following 1h treatment with CHX. Overlaps with disease biomarkers for cancer, growth retardation and multiple organ-specific diseases were identified. Conclusions: Biomarkers for normal, acute cellular responses overlap with disease-state biomarkers, warranting further study.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent10
dc.format.extent1459608
dc.identifier.doi10.1093/qjmed/hcae235
dc.identifier.issn1460-2725
dc.identifier.otherPURE: 156370598
dc.identifier.otherPURE UUID: 99ff150b-4c36-47bc-8fdf-824d4a723c0e
dc.identifier.otherScopus: 105023546309
dc.identifier.otherPubMed: 39658243
dc.identifier.otherWOS: 001404190400001
dc.identifier.otherORCID: /0000-0002-1422-1336/work/207951048
dc.identifier.urihttp://hdl.handle.net/10362/201124
dc.identifier.urlhttps://www.scopus.com/pages/publications/105023546309
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGeneral Medicine
dc.subjectSDG 3 - Good Health and Well-being
dc.titleAcute endothelial stresses identify microRNA let-7b-5p and non-coding SLC11A2 (NRAMP2/DMT1) exon as biomarkers that overlap with those detected in malignant and non-malignant diseasesen
dc.typejournal article
degois.publication.firstPage679
degois.publication.issue9
degois.publication.lastPage688
degois.publication.titleQJM: An International Journal of Medicine
degois.publication.volume118
dspace.entity.typePublication
rcaap.rightsopenAccess

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