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.

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.

• Authors: Mengmeng Jiang, Wenwen Zhang, Rui Zhang, Pengpeng Liu, Yingnan Ye, Wenwen Yu, Xiaojing Guo, Jinpu Yu
• Journal: Oncogene (Oncogene) Vol. 39 Issue 24 Pg. 4681-4694 (06 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32398867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN9 microRNA, mouse
• MIRN92 microRNA, human
• MIrn181 microRNA, human
• MicroRNAs
• Molecular Chaperones
• PIAS3 protein, human
• Pias3 protein, mouse
• Protein Inhibitors of Activated STAT
• SOCS3 protein, human
• Socs3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• mirn181 microRNA, mouse

Topics

• Animals
• Breast Neoplasms (genetics, immunology, pathology)
• Exosomes (genetics, immunology, pathology)
• Female
• Humans
• Mammary Neoplasms, Experimental (genetics, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• MicroRNAs (genetics, immunology)
• Molecular Chaperones (genetics, immunology)
• Myeloid-Derived Suppressor Cells (immunology, pathology)
• Protein Inhibitors of Activated STAT (genetics, immunology)
• Suppressor of Cytokine Signaling 3 Protein (genetics, immunology)