Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer
Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer
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癌症外泌体来源的 miR-9 和 miR-181a 分别通过干扰乳腺癌中的 SOCS3 和 PIAS3 促进早期 MDSC 的发育
DOI：
10.1038/s41388-020-1322-4
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发表时间：
2020-05-12
期刊：
影响因子：
8
通讯作者：
Yu, Jinpu
中科院分区：
文献类型：
--
作者：
Jiang, Mengmeng;Zhang, Wenwen;Yu, Jinpu
我们先前发现，乳腺癌中早期髓源性抑制细胞（eMDSC）的发展与高IL-6（IL-6（高））表达与JAK/STAT信号通路的SOCS 3缺陷依赖性过度激活相关。然而，调控机制尚未阐明。在本研究中，我们的目的是研究癌症外泌体衍生的miRNA介导的转录后调控如何影响JAK/STAT信号通路和eMDSCs的发育。使用miRNA微阵列，我们筛选了miR-9和miR-181 a，它们在eMDSC中唯一上调，并与SOCS 3表达呈负相关。我们发现这两种miRNA都促进了未成熟eMDSC的扩增，并强烈抑制了小鼠和人类的T细胞免疫。此外，miR-9和miR-181 a通过增强eMDSC原位浸润促进4 T1肿瘤生长和免疫逃逸。但miR-9和miR-181 a通过分别抑制SOCS 3和PIAS 3（JAK/STAT信号通路负反馈回路中的两个关键调节因子）来刺激eMDSC发育。eMDSC中升高的miR-9和miR-181 a来源于肿瘤来源的外泌体，阻断外泌体释放可以完全减弱miRNA介导的对eMDSC发育的调节。总之，我们的研究结果表明，肿瘤外泌体来源的miR-9和miR-181 a分别通过靶向SOCS 3和PIAS 3激活JAK/STAT信号通路，从而促进eMDSC的扩增，这可能为IL-6（高）乳腺癌治疗提供潜在的治疗靶点。
We previously identified that the development of early-stage myeloid-derived suppressor cells (eMDSCs) in breast cancer with high IL-6 (IL-6(high)) expression was correlated with the SOCS3 deficiency-dependent hyperactivation of the JAK/STAT signaling pathway. However, the regulatory mechanisms have not yet been elucidated. In this study, we aimed to investigate how the posttranscriptional regulation mediated by cancer exosome-derived miRNAs affected the JAK/STAT signaling pathway and the development of eMDSCs. Using miRNA microarray, we screened miR-9 and miR-181a which were exclusively upregulated in eMDSCs and inversely associated with SOCS3 expression. We found both miRNAs promoted the amplification of immature eMDSCs with the strong suppression on T-cell immunity in mice and humans. Furthermore, miR-9 and miR-181a promoted 4T1 tumor growth and immune escape via enhancing eMDSCs infiltration in situ. But miR-9 and miR-181a stimulated eMDSCs development by separately inhibiting SOCS3 and PIAS3, two crucial regulators in the negative feedback loop of the JAK/STAT signaling pathway. Elevated miR-9 and miR-181a in eMDSCs was derived from tumor-derived exosomes, and blocking the exosome release could fully attenuate the miRNA-mediated regulation on eMDSCs development. In summary, our findings indicated that tumor exosome-derived miR-9 and miR-181a activated the JAK/STAT signaling pathway via targeting SOCS3 and PIAS3, respectively, and thus promoted the expansion of eMDSCs which might provide potential therapeutic target for IL-6(high) breast cancer treatment.