Lian Hongyu, Yu Miao, Li Qi, Xiao Jiayi, Tang Xin, Zhang Bin, Liu Dongxue, Xu Yongliang, Dong Mo, Li Zitao, Yao Lihong, Li Caijuan
Department of Orthopedic Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, China.
Department of Ultrasound, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, China.
Hum Cell. 2025 May 30;38(4):114. doi: 10.1007/s13577-025-01232-9.
Hypoxia is a critical mechanism within the microenvironment of tumors. Exosomes, serve as conduits for intercellular communication and transport the biomolecule miRNA by facilitating intercellular signal exchange, which partially regulate cancer metastasis. Our research investigated whether the role of hypoxic breast cancer cell-derived exosomal miR-143-3p in cancer progression. Real-time PCR explored miR-143-3p expression in hypoxia breast cancer cell-derived exosomes. Co-culturing of breast cancer with hypoxia exosome-primed M0 macrophages, transwell detected the invasiveness of breast cancer cells. Western blot showed the effect of hypoxia exosomes on the levels of M2 makers in macrophages and the epithelial-mesenchymal transition (EMT) indicators in breast cancer cells. Bioinformatics prediction and dual luciferase reporter assay determined the interaction between miR-143-3p and RICTOR. We found that exosomal miR-143-3p expression was downregulated in hypoxic conditions. Hypoxia breast cancer cell-derived exosomal miR-143-3p negatively correlated with the presentation of the M2 macrophage marker CD206 and regulated the levels of Arg-1, CD206 and CD163 mRNA levels. In addition, hypoxia exosome-mediated polarization of M2 macrophages promotes breast cancer cell migration and invasion. Mechanistically, miR-143-3p acted antagonistically with RICTOR, thereby suppressing macrophage M2 polarization. In summary, our study reveals that the hypoxia downregulates the exosomal miR-143-3p derived from breast cancer cells to increase macrophage RICTOR expression, thereby promoting M2 macrophage polarization to enhance breast cancer cell invasiveness, suggesting that miR-143-3p may be a candidate molecule for microRNA alternative therapy in breast cancer.
缺氧是肿瘤微环境中的一种关键机制。外泌体作为细胞间通讯的管道，通过促进细胞间信号交换来运输生物分子miRNA，这在一定程度上调节癌症转移。我们的研究调查了缺氧乳腺癌细胞衍生的外泌体miR-143-3p在癌症进展中的作用。实时PCR检测缺氧乳腺癌细胞衍生外泌体中miR-143-3p的表达。将乳腺癌细胞与经缺氧外泌体预处理的M0巨噬细胞共培养，通过Transwell检测乳腺癌细胞的侵袭能力。蛋白质免疫印迹法显示缺氧外泌体对巨噬细胞中M2标志物水平以及乳腺癌细胞中上皮-间质转化（EMT）指标的影响。生物信息学预测和双荧光素酶报告基因检测确定了miR-143-3p与RICTOR之间的相互作用。我们发现缺氧条件下外泌体miR-143-3p的表达下调。缺氧乳腺癌细胞衍生的外泌体miR-143-3p与M2巨噬细胞标志物CD206的表达呈负相关，并调节精氨酸酶-1、CD206和CD163 mRNA的水平。此外，缺氧外泌体介导的M2巨噬细胞极化促进乳腺癌细胞的迁移和侵袭。机制上，miR-143-3p与RICTOR起拮抗作用，从而抑制巨噬细胞M2极化。总之，我们的研究表明，缺氧下调乳腺癌细胞衍生的外泌体miR-143-3p，以增加巨噬细胞RICTOR的表达，从而促进M2巨噬细胞极化，增强乳腺癌细胞的侵袭性，提示miR-143-3p可能是乳腺癌微小RNA替代疗法的候选分子。
