ArticleQJM : monthly journal of the Association of Physicians2025
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.
Article in QJM : monthly journal of the Association of Physicians, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundDisease 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.
aimTo model two under-explored acute cellular stresses for blood-exposed cells, and cross-reference to known biomarkers of disease.
methodsNormal primary human endothelial cells (ECs) were treated for 1-6 h with cycloheximide (CHX) 100 μg/ml to inhibit protein translation and nonsense-mediated decay (modelling the integrated stress response), or 10 μmol/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 1 h 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.
resultsmiRNAs fell transiently at 1 h after 10 μmol/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 6 h 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 1 h iron, and exon 3B of the SLC11A2 (NRAMP2/DMT1)-encoded iron/copper transporter as a novel exon most consistently stabilized following 1 h treatment with CHX. Overlaps with disease biomarkers for cancer, growth retardation and multiple organ-specific diseases were identified.
conclusionsBiomarkers for normal, acute cellular responses overlap with disease-state biomarkers, warranting further study.
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