College of pharmaceutical science, Zhejiang University, Hangzhou, 310058, China.
Department of Clinical Pharmacology, Affiliated Hangzhou First People's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China.
J Nanobiotechnology. 2023 Nov 14;21(1):422. doi: 10.1186/s12951-023-02190-w.
Despite being a common malignant tumor, the molecular mechanism underlying the initiation and progression of triple-negative breast cancers (TNBCs) remain unclear. Tumor-associated macrophages (TAMs) are often polarized into a pro-tumor phenotype and are associated with a poor prognosis of TNBCs. Exosomes, important mediators of cell-cell communication, can be actively secreted by donor cells to reprogram recipient cells. The functions and molecular mechanisms of tumor cell-derived exosomes in TNBCs progression and TAMs reprogramming urgently need to be further explored.
We demonstrated that tumor cell-derived exosomes enriched with miR-184-3p were taken up by macrophages to inhibit JNK signaling pathway by targeting EGR1, thereby inducing M2 polarization of macrophages and synergistically promoting tumor progression. Nanoparticles loaded with oncogene c-Myc inhibitor JQ1 could suppress the polarization process by reducing Rac1-related exosome uptake by macrophage. More importantly, it was found for the first time that tumor-suppressive miR-184-3p was actively sorted into exosomes by binding to RNA-binding protein heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), thus facilitating tumor cell proliferation and metastasis by relieving the inhibitory effect of miR-184-3p on Mastermind-like 1 (MAML1). Overexpressing miR-184-3p in tumor cells and simultaneously knocking down hnRNPA2B1 to block its secretion through exosomes could effectively inhibit tumor growth and metastasis.
Our study revealed that hnRNPA2B1-mediated exosomal transfer of tumor-suppressive miR-184-3p from breast cancer cells to macrophages was an important mediator of TNBCs progression, providing new insights into TNBCs pathogenesis and therapeutic strategies.
尽管三阴性乳腺癌（TNBC）是一种常见的恶性肿瘤，但它的发生和发展的分子机制仍不清楚。肿瘤相关巨噬细胞（TAMs）通常极化为促肿瘤表型，并与 TNBC 的预后不良相关。外泌体是细胞间通讯的重要介质，可被供体细胞主动分泌，从而重新编程受体细胞。肿瘤细胞衍生的外泌体在 TNBC 进展和 TAMs 重编程中的功能和分子机制亟待进一步探索。
我们证明，富含 miR-184-3p 的肿瘤细胞衍生的外泌体被巨噬细胞摄取，通过靶向 EGR1 抑制 JNK 信号通路，从而诱导巨噬细胞的 M2 极化，并协同促进肿瘤进展。负载癌基因 c-Myc 抑制剂 JQ1 的纳米颗粒通过减少 Rac1 相关外泌体被巨噬细胞摄取，可抑制极化过程。更重要的是，我们首次发现，肿瘤抑制性 miR-184-3p 通过与 RNA 结合蛋白异质核核糖核蛋白 A2B1（hnRNPA2B1）结合被主动分选到外泌体中，从而通过解除 miR-184-3p 对 Mastermind-like 1（MAML1）的抑制作用，促进肿瘤细胞的增殖和转移。在肿瘤细胞中过表达 miR-184-3p 并同时敲低 hnRNPA2B1 以阻断其通过外泌体的分泌，可有效抑制肿瘤生长和转移。
本研究揭示了 hnRNPA2B1 介导的肿瘤抑制性 miR-184-3p 从乳腺癌细胞到巨噬细胞的外泌体转移是 TNBC 进展的一个重要介质，为 TNBC 的发病机制和治疗策略提供了新的见解。
