Zheng Li, Mo Juanfen, He Xuesong, Xu Qi, Bao Yi, Wu Jiayuan
The Key Laboratory, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, People's Republic of China.
Department of Breast Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, People's Republic of China.
Med Oncol. 2025 Jun 25;42(8):280. doi: 10.1007/s12032-025-02836-9.
Exosomal long non-coding RNAs (lncRNAs) play crucial roles in breast cancer progression. However, the mechanisms by which hypoxia-induced exosomes mediate angiogenesis through lncRNAs in the tumor microenvironment remain largely unexplored. In this study, exosomes were isolated and characterized from MDA-MB-231 breast cancer cells under normoxic and hypoxic conditions. Hypoxia-induced exosomes (Hyp-exo) were shown to significantly promote angiogenesis. Microarray analysis revealed that lnc-MTRNR2L12-3 was highly enriched in Hyp-exo compared to normoxic exosomes (NC-exo). Functional studies, both in vitro and in vivo, demonstrated that exosomal lnc-MTRNR2L12-3 derived from hypoxic breast cancer cells substantially enhanced angiogenesis. Mechanistically, PCR array and western blot analysis confirmed that silencing lnc-MTRNR2L12-3 inhibited Src/FAK signaling pathway activation in HUVECs, while hypoxia-induced exosomes effectively rescued this suppression. Overall, hypoxia-induced breast cancer exosomes deliver lnc-MTRNR2L12-3 to endothelial cells, promoting angiogenesis through the Src/FAK signaling pathway. These findings provide new insights into targeting angiogenesis in the tumor microenvironment for breast cancer therapy.
外泌体长链非编码RNA（lncRNAs）在乳腺癌进展中发挥着关键作用。然而，缺氧诱导的外泌体通过lncRNAs在肿瘤微环境中介导血管生成的机制在很大程度上仍未被探索。在本研究中，从常氧和缺氧条件下的MDA-MB-231乳腺癌细胞中分离并鉴定了外泌体。结果显示，缺氧诱导的外泌体（Hyp-exo）能显著促进血管生成。微阵列分析表明，与常氧外泌体（NC-exo）相比，lnc-MTRNR2L12-3在Hyp-exo中高度富集。体外和体内的功能研究均表明，源自缺氧乳腺癌细胞的外泌体lnc-MTRNR2L12-3能显著增强血管生成。从机制上来说，PCR阵列和蛋白质印迹分析证实，沉默lnc-MTRNR2L12-3可抑制人脐静脉内皮细胞（HUVECs）中Src/FAK信号通路的激活，而缺氧诱导的外泌体能有效挽救这种抑制作用。总体而言，缺氧诱导的乳腺癌外泌体将lnc-MTRNR2L12-3传递给内皮细胞，通过Src/FAK信号通路促进血管生成。这些发现为针对肿瘤微环境中的血管生成进行乳腺癌治疗提供了新的见解。
