Key Points Tumor exosome–derived miR-183 regulates macrophage cytokine production. miR-183 contributes to metastatic spread of breast tumors in vivo. Visual Abstract Tumor-associated macrophages (TAMs) play a critical role in the tumor inflammatory microenvironment and facilitate tumor growth and metastasis. Most types of tumors aberrantly express microRNAs (miRNAs), which can be transferred between cells by exosomes and can regulate gene expression in recipient cells, but it remains unclear whether tumor-derived miRNAs are transferred by exosomes and regulate the TAM phenotype. We report that mouse 4T1 breast cancer cell–derived exosomes enhanced TAM expression of IL-1β, IL-6, and TNF-α and that inhibition of 4T1-cell exosome secretion through short hairpin RNA–mediated Rab27a/b depletion repressed tumor growth and metastasis and markedly downregulated IL-1β, IL-6, and TNF-α in a 4T1 breast tumor model. Furthermore, miRNA expression profiling revealed that three miRNAs (miR-100-5p, miR-183-5p, and miR-125b-1-3p) were considerably more abundant in 4T1 cell exosomes than in mouse bone marrow–derived macrophages, indicating potential exosome-mediated transfer of the miRNAs, and, notably, miR-183-5p was found to be transferred from 4T1 cells to macrophages through exosomes. Moreover, PPP2CA was verified as an miR-183-5p target gene, and PPP2CA downregulation enhanced NF-κB signaling and promoted macrophage expression of IL-1β, IL-6, and TNF-α. Lastly, when miR-183-5p was downregulated in exosomes through miR-183-5p sponge expression in 4T1 cells, these 4T1-derived exosomes triggered diminished p65 phosphorylation and IL-1β, IL-6, and TNF-α secretion, and the miRNA downregulation also led to repression of tumor growth and metastasis in the 4T1 breast tumor model in vivo. Thus, miR-183-5p expressed in tumor cells was transferred to macrophages by exosomes and promoted the secretion of proinflammatory cytokines by inhibiting PPP2CA expression, which contributed to tumor progression in a breast cancer model.

中文翻译：

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小鼠 4T1 乳腺癌细胞衍生的外泌体通过 miR-183 在巨噬细胞中诱导促炎细胞因子的产生

关键点肿瘤外泌体衍生的 miR-183 调节巨噬细胞细胞因子的产生。miR-183 有助于体内乳腺肿瘤的转移扩散。视觉摘要 肿瘤相关巨噬细胞 (TAM) 在肿瘤炎症微环境中发挥关键作用，促进肿瘤生长和转移。大多数类型的肿瘤异常表达微小RNA（miRNA），其可以通过外泌体在细胞之间转移并可以调节受体细胞中的基因表达，但尚不清楚肿瘤衍生的miRNA是否通过外泌体转移并调节TAM表型。我们报告说，小鼠 4T1 乳腺癌细胞来源的外泌体增强了 IL-1β、IL-6、和 TNF-α 以及通过短发夹 RNA 介导的 Rab27a/b 消耗抑制 4T1 细胞外泌体分泌抑制肿瘤生长和转移，并显着下调 4T1 乳腺肿瘤模型中的 IL-1β、IL-6 和 TNF-α。此外，miRNA 表达谱显示，3 种 miRNA（miR-100-5p、miR-183-5p 和 miR-125b-1-3p）在 4T1 细胞外泌体中的含量远高于小鼠骨髓来源的巨噬细胞，表明其具有潜力外泌体介导的 miRNA 转移，尤其是 miR-183-5p 被发现通过外泌体从 4T1 细胞转移到巨噬细胞。此外，PPP2CA 被证实为 miR-183-5p 靶基因，PPP2CA 下调增强了 NF-κB 信号传导并促进了巨噬细胞 IL-1β、IL-6 和 TNF-α 的表达。最后，当 miR-183-5p 在外泌体中通过 4T1 细胞中的 miR-183-5p 海绵表达下调时，这些 4T1 衍生的外泌体引发 p65 磷酸化和 IL-1β、IL-6 和 TNF-α 分泌减少，以及 miRNA 下调还导致体内 4T1 乳腺肿瘤模型中肿瘤生长和转移的抑制。因此，肿瘤细胞中表达的 miR-183-5p 被外泌体转移到巨噬细胞，并通过抑制 PPP2CA 表达促进促炎细胞因子的分泌，这有助于乳腺癌模型中的肿瘤进展。