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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
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Resumo(s)
Background: 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.
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Publisher Copyright: © 2025 The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians.
Palavras-chave
General Medicine SDG 3 - Good Health and Well-being