Lim Jiwoo, Kang Mia, Ahn Young-Ho, Cho Min-Sun, Lee Jin Hwa, Kang Jihee Lee, Choi Youn-Hee
Department of Physiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea.
Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea.
Cancers (Basel). 2025 Jun 10;17(12):1929. doi: 10.3390/cancers17121929.
Brain metastasis occurs in 40-50% of lung cancer patients and is associated with poor prognosis. This study aimed to identify potential exosomal biomarkers for the early detection of brain metastasis in lung cancer using a comprehensive multi-omics approach.
Using a lung cancer mouse model, which develops brain metastasis, we collected serum samples at different stages (control, 6 weeks for lung cancer, and 10 weeks for brain metastasis). We profiled the contents of serum-derived exosomes using small RNA sequencing and LC-MS/MS proteomic analysis, and assessed the clinical relevance of candidate biomarkers using publicly available patient datasets.
RNA sequencing identified 11 differentially expressed miRNAs across disease progression, with miR-206-3p showing significant upregulation during brain metastasis. Pathway analysis of miR-206-3p targets revealed enrichment in cancer-related pathways, including Hippo, MAPK, Ras, and PI3K-Akt signaling. Proteomic analysis revealed 77 proteins specifically upregulated in the brain metastasis stage, with vinculin (VCL) emerging as a promising marker. While VCL expression decreased in lung tissues and showed no significant changes in brain tissues, its levels were significantly elevated in serum-derived exosomes during brain metastasis. Clinical database analysis revealed that higher VCL expression correlated with poor patient survival.
Our study identified exosomal miR-206-3p and VCL as promising non-invasive biomarkers for brain metastasis in lung cancer using the mouse model. These findings provide new opportunities for early detection and monitoring of brain metastasis, potentially enabling timely therapeutic intervention.
脑转移发生在40%-50%的肺癌患者中，且与预后不良相关。本研究旨在使用全面的多组学方法鉴定用于肺癌脑转移早期检测的潜在外泌体生物标志物。
利用一种会发生脑转移的肺癌小鼠模型，我们在不同阶段（对照组、肺癌6周、脑转移10周）收集血清样本。我们使用小RNA测序和液相色谱-串联质谱蛋白质组分析对血清来源的外泌体内容物进行了分析，并使用公开可用的患者数据集评估了候选生物标志物的临床相关性。
RNA测序鉴定出11种在疾病进展过程中差异表达的miRNA，其中miR-206-3p在脑转移期间显著上调。对miR-206-3p靶标的通路分析显示，其在癌症相关通路中富集，包括Hippo、MAPK、Ras和PI3K-Akt信号通路。蛋白质组分析显示，77种蛋白质在脑转移阶段特异性上调，其中纽蛋白（VCL）成为一个有前景的标志物。虽然VCL在肺组织中的表达降低，在脑组织中无显著变化，但其水平在脑转移期间血清来源的外泌体中显著升高。临床数据库分析显示，较高的VCL表达与患者较差的生存率相关。
我们的研究使用小鼠模型鉴定出外泌体miR-206-3p和VCL作为肺癌脑转移有前景的非侵入性生物标志物。这些发现为脑转移的早期检测和监测提供了新机会，有可能实现及时的治疗干预。
