Li Zhou, Jin Ke, Shanlan Zhang, Sufang Xiao, Hui Zhang, Shan Liu, Li Liu, Mingan Liu, Zuohua Lu, Songguo Zheng
{"title":"Elevated miR-103b in exosomes derived from brain-metastatic triple-negative breast cancer cells remodels the brain pre-metastatic niche (PMN).","authors":"Li Zhou, Jin Ke, Shanlan Zhang, Sufang Xiao, Hui Zhang, Shan Liu, Li Liu, Mingan Liu, Zuohua Lu, Songguo Zheng","doi":"10.1080/15384047.2026.2725357","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer with high brain metastatic (BM) potential. Tumor-derived exosomes are implicated as key modulators during the formation of the pre-metastatic niche (PMN). However, the regulation of TNBC-BM-derived exosomes on brain PMN remains enigmatic.</p><p><strong>Methods: </strong>The morphology and uptake of exosomes were identified using transmission electron microscopy and live-cell imaging, respectively. Differentially secreted miRNAs and mRNA were identified using high-throughput sequencing. The permeability of the blood‒brain barrier (BBB) and tight junction integrity were examined using immunofluorescence staining. Cell viability was examined using the CCK-8 assay. The apoptosis and intracellular ROS were investigated using fluorescence staining. The expression of mRNAs was examined using qPCR.</p><p><strong>Results: </strong>miR-103b was significantly increased in exosomes derived from TNBC-BM cells. miR-103b compromised the tight junctions of HUVECs and increased BBB permeability in mice. Additionally, miR-103b promoted apoptosis and increased intracellular ROS in HUVECs and U251 cells, two cell lines commonly used as surrogates for brain microvascular endothelial cells and astrocytes, respectively. miR-103b-regulated differentially expressed genes modulated tight junction, apoptosis, oxidative stress, inflammation, and metabolism. Target analysis identified 216 targets of miR-103b, among which hub targets were associated with biological processes involved in maintaining the BBB and the glucose metabolism signaling pathway.</p><p><strong>Conclusion: </strong>Collectively, our findings for the first time reveal that exosomal miR-103b from TNBC-BM cells potentially regulates the two major cellular constituents of the brain PMN, highlighting its role in the formation of the brain PMN during TNBC-BM and its potential as a promising therapeutic target.</p>","PeriodicalId":9536,"journal":{"name":"Cancer Biology & Therapy","volume":"27 1","pages":"2725357"},"PeriodicalIF":5.7000,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618856/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Biology & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/15384047.2026.2725357","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/9/25 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer with high brain metastatic (BM) potential. Tumor-derived exosomes are implicated as key modulators during the formation of the pre-metastatic niche (PMN). However, the regulation of TNBC-BM-derived exosomes on brain PMN remains enigmatic.
Methods: The morphology and uptake of exosomes were identified using transmission electron microscopy and live-cell imaging, respectively. Differentially secreted miRNAs and mRNA were identified using high-throughput sequencing. The permeability of the blood‒brain barrier (BBB) and tight junction integrity were examined using immunofluorescence staining. Cell viability was examined using the CCK-8 assay. The apoptosis and intracellular ROS were investigated using fluorescence staining. The expression of mRNAs was examined using qPCR.
Results: miR-103b was significantly increased in exosomes derived from TNBC-BM cells. miR-103b compromised the tight junctions of HUVECs and increased BBB permeability in mice. Additionally, miR-103b promoted apoptosis and increased intracellular ROS in HUVECs and U251 cells, two cell lines commonly used as surrogates for brain microvascular endothelial cells and astrocytes, respectively. miR-103b-regulated differentially expressed genes modulated tight junction, apoptosis, oxidative stress, inflammation, and metabolism. Target analysis identified 216 targets of miR-103b, among which hub targets were associated with biological processes involved in maintaining the BBB and the glucose metabolism signaling pathway.
Conclusion: Collectively, our findings for the first time reveal that exosomal miR-103b from TNBC-BM cells potentially regulates the two major cellular constituents of the brain PMN, highlighting its role in the formation of the brain PMN during TNBC-BM and its potential as a promising therapeutic target.
期刊介绍：
Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
