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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

Oncogene volume 39, pages 4681–4694 (2020)Cite this article

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Abstract

We previously identified that the development of early-stage myeloid-derived suppressor cells (eMDSCs) in breast cancer with high IL-6 (IL-6high) 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-6high breast cancer treatment.

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Fig. 1: MiR-9 and miR-181a were inversely correlated with IL-6 dependent SOCS3 deficiency in mice eMDSCs.
Fig. 2: MiR-9 and miR-181a promoted the amplification and immunosuppressive function of mice eMDSCs.
Fig. 3: MiR-9 and miR-181a activated JAK/STAT signaling pathway by targeting SOCS3 and PIAS3 in mice eMDSCs, respectively.
Fig. 4: MiR-9 and miR-181a promoted tumor growth in 4T1-bearing mice via enhancing eMDSCs infiltration and inhibiting T-cell immunity in situ.
Fig. 5: MiR-9 and miR-181a promoted the development and immunosuppressive function of human eMDSCs.
Fig. 6: Both miR-9/SOCS3 and miR-181a/PIAS3 activated JAK/STAT signaling pathway in human eMDSCs in vitro.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Grant No.81872143, 81472473, 81772840), National Science and Technology Support Program of China (Grant No.2015BAI12B15), National Science and Technology Major Project (Grant No.2018ZX09201-015), Project of Science and Technology of Tianjin (Grant No.13ZCZCSY20300, 18JCQNJC82700) and Key Project of Tianjin Health and Family Planning Commission (Grant No.16KG126). We appreciate the efforts of Dr Juntian Liu and Dr Shixia Li of Department of Preventive Health Screening Center in sample collection. We thank Dr Xiubao Ren of Department of Biotherapy for support of Flow cytometry. We also thank Prof Weijia Zhang of Department of Medicine of Icahn School of Medicine at Mount Sinai for constructive comments to our manuscript.

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  1. These authors contributed equally: Mengmeng Jiang, Wenwen Zhang

Authors and Affiliations

  1. Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

    Mengmeng Jiang, Wenwen Zhang, Rui Zhang, Pengpeng Liu, Yingnan Ye & Jinpu Yu

  2. Department of Oncology, Tianjin Third Central Hospital, Tianjin, China

    Mengmeng Jiang

  3. Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Wenwen Zhang, Rui Zhang, Pengpeng Liu, Yingnan Ye, Wenwen Yu & Jinpu Yu

  4. Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China

    Wenwen Yu & Jinpu Yu

  5. Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Xiaojing Guo

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Jiang, M., Zhang, W., Zhang, R. et al. 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. Oncogene 39, 4681–4694 (2020). https://doi.org/10.1038/s41388-020-1322-4

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