Hypoxic breast cancer cell-derived exosomal miR-143-3p targets RICTOR to regulate M2 macrophage polarization, thereby modulating cancer cell invasiveness

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Abstract
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.
Funding Information
  • National Natural Science Foundation of China (82171966)
  • Torch Program of Mudanjiang Medical University (2022-MYHJ-007)
  • Young Innovative Talents Training Program of Regular Undergraduate Colleges and Universities in Heilongjiang Province (UNPYSCT-2020065)

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