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

Zhu, Kaitao, Yao, Hongru, Hei, Jilong, Li, Shiwei, Ye, Tongxin, Jiang, WenG, Wang, Shuwen, Luo, Zhuojun, Martin, Tracey ORCID: https://orcid.org/0000-0003-2690-4908, Zhou, Jie and Zhang, Shanyi 2025. 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. Journal of Translational Medicine 23 (1) , 1333. 10.1186/s12967-025-07372-8

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Abstract

Background: Tumor-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. Methods: A 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. Results: Highly 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. Conclusions: Our 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. Graphical Abstract:

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	BioMed Central
Date of First Compliant Deposit:	26 November 2025
Date of Acceptance:	22 October 2025
Last Modified:	26 Nov 2025 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/182678

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