ArticleJournal of translational medicine2025
Tumor exosomal miR-221-3p induces glycolysis through the LIFR/GLUT1 pathway to destroy the cerebral vascular endothelial cell barrier and promote breast cancer brain metastasis.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Elevated miR-103b in exosomes derived from brain-metastatic triple-negative breast cancer cells remodels the brain pre-metastatic niche (PMN).Cancer biology & therapy · 2026Article
- Boundary cap neural crest stem cells exhibit remarkable resilience to environmental stressors associated with International Space Station mission.NPJ microgravity · 2026Article
- Endoplasmic reticulum stress in brain metastatic cascade.NPJ precision oncology · 2026Review
- Lactate-lactylation in tumor angiogenesis and progression: mechanisms, biomarker potential, and therapeutic implications.Biomarker research · 2026Review
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11 authors.
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Abstract
backgroundTumor-derived exosomal microRNAs mediate intercellular communication between malignant cells and distant organs and play a pivotal role in metastatic dissemination. Breast cancer brain metastasis (BCBM) poses a significant clinical challenge, with endothelial barrier dysfunction representing a critical yet poorly understood step in metastatic progression.
methodsA physiologically relevant in vitro blood‒brain barrier (BBB) model was established to evaluate exosomal functions. Mechanistic investigations included qPCR and western blotting for miR-221-3p, along with protein expression profiling, immunofluorescence-based tight junction protein visualization, apoptosis detection via annexin V/PI staining, EdU assays for proliferation quantification, and transendothelial migration assessments. To validate the underlying mechanism, ALIX/HRS were silenced to inhibit exosome secretion, and miR-221-3p antagonists were applied. Clinical relevance was assessed by analyzing plasma miR-221-3p levels in breast cancer (BC) patients.
resultsHighly invasive breast cancer-derived exosomal miR-221-3p induced glycolysis and lactic acid accumulation in brain microvascular endothelial cells by targeting the leukemia inhibitory factor receptor (LIFR), leading to endothelial barrier destruction and reduced tight junction protein expression. This significantly enhanced endothelial barrier permeability and tumor cell transendothelial migration capacity. Silencing ALIX/HRS or antagonizing miR-221-3p markedly reversed these effects.
conclusionsOur findings indicate that BC can target LIFR in hCMEC/D3 cells via exosomal miR-221-3p, thereby promoting glycolysis and inhibiting the expression of tight junction proteins, which facilitates tumor metastasis.
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