Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China; Department of Life Sciences, Bengbu Medical University, Anhui 233030, China.
Anhui Province Key Laboratory of Cancer Translational Medicine (Bengbu Medical University), Anhui 233030, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt B):113168. doi: 10.1016/j.intimp.2024.113168. Epub 2024 Sep 18.
The most frequent cancer in women to be diagnosed is breast cancer, and chemotherapy's ability to be effective is still significantly hampered by drug resistance. Tumor-derived exosomes play a significant role in drug resistance, immunological modulation, metastasis, and tumor proliferation. In this work, the differential miRNAs in the exosomes of drug-resistant and susceptible breast cancer cell lines were screened using miRNA-seq. It was demonstrated that drug-resistant human breast cancer cells and their exosomes expressed more miR-99b-3p than did susceptible cells and their exosomes. While drug-resistant cells' migration and paclitaxel resistance can be inhibited by driving down the expression of miR-99b-3p in those cells, exosomes containing miR-99b-3p from those cells can help susceptible cells migrate and become resistant. miR-99b-3p affects cell migration and paclitaxel resistance by targeting PPP2CA to promote AKT/mTOR phosphorylation. The drug-resistant cell exosome miR-99b-3p can be taken up by macrophages and affect the drug resistance and migration ability of sensitive cells by promoting the M2 polarization of macrophages. Downregulating miR-99b-3p has been shown in vivo to reverse macrophage M2 polarization, suppress tumor development, and prevent treatment resistance. The present study shows that drug-resistant cell exosomes miR-99b-3p can directly influence the migration, proliferation, and paclitaxel sensitivity of sensitive cells via PPP2CA. Additionally, the exosomes from drug-resistant cells can influence the polarization of macrophage M2 in the tumor microenvironment, which can also have an impact on the proliferation, migration, and paclitaxel sensitivity of sensitive cells.
女性最常被诊断出的癌症是乳腺癌，而化疗的有效性仍然受到耐药性的严重阻碍。肿瘤来源的外泌体在耐药性、免疫调节、转移和肿瘤增殖中发挥重要作用。在这项工作中，使用 miRNA-seq 筛选了耐药和敏感乳腺癌细胞系中外泌体中的差异 miRNA。结果表明，耐药性人乳腺癌细胞及其外泌体表达的 miR-99b-3p 多于敏感性细胞及其外泌体。虽然通过下调这些细胞中 miR-99b-3p 的表达可以抑制耐药细胞的迁移和紫杉醇耐药性，但来自这些细胞的含有 miR-99b-3p 的外泌体可以帮助敏感细胞迁移并产生耐药性。miR-99b-3p 通过靶向 PPP2CA 促进 AKT/mTOR 磷酸化来影响细胞迁移和紫杉醇耐药性。耐药细胞外泌体 miR-99b-3p 可被巨噬细胞摄取，并通过促进巨噬细胞 M2 极化来影响敏感细胞的耐药性和迁移能力。体内研究表明，下调 miR-99b-3p 可逆转巨噬细胞 M2 极化，抑制肿瘤发展，并防止治疗耐药性。本研究表明，耐药细胞外泌体 miR-99b-3p 可通过 PPP2CA 直接影响敏感细胞的迁移、增殖和紫杉醇敏感性。此外，耐药细胞来源的外泌体还可以影响肿瘤微环境中巨噬细胞 M2 的极化，从而对敏感细胞的增殖、迁移和紫杉醇敏感性产生影响。
