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Cancer Res. 2019 Apr 23. pii: canres.2659.2018. doi: 10.1158/0008-5472.CAN-18-2659. [Epub ahead of print]

MicroRNA-92 expression in CD133+ melanoma stem cells regulates immunosuppression in the tumor microenvironment via integrin-dependent activation of TGF-β.

Author information

1
Pathology, Microbiology, and Immunology, University of South Carolina.
2
Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine.
3
Pathology Mircobiology and Immunology, University of South Carolina.
4
Pathology, University of South Carolina Mitzi.Nagarkatti@uscmed.sc.edu.

Abstract

In addition to being refractory to treatment, melanoma cancer stem cells (CSC) are known to suppress host anti-tumor immunity, the underlying mechanisms of which need further elucidation. In this study, we established a novel role for microRNA-92 (miR-92) and its associated gene networks in immunosuppression. CSCs were isolated from the B16-F10 murine melanoma cell line based on expression of the putative CSC marker CD133 (Prominin-1). CD133+ cells were functionally distinct from CD133- cells and showed increased proliferation in vitro and enhanced tumorigenesis in vivo. CD133+ CSCs also exhibited a greater capacity to recruit immunosuppressive cell types during tumor formation, including FoxP3+ Tregs, myeloid-derived suppressor cells (MDSC) and M2 macrophages. Using microarray technology, we identified several miRs that were significantly downregulated in CD133+ cells compared to CD133- cells, including miR-92. Decreased expression of miR-92 in CSCs led to higher expression of target molecules integrin αV and α5 subunits, which in turn enhanced TGF-β activation as evidenced by increased phosphorylation of SMAD2. CD133+ cells transfected with miR-92a mimic and injected in vivo showed significantly decreased tumor burden, which was associated with reduced immunosuppressive phenotype intratumorally. Using the TCGA database of melanoma patients, we also noted a positive correlation between integrin α5 and TGF-β1 expression levels and an inverse association between miR-92 expression and integrin alpha subunit expression. Collectively, the current study suggests that a miR-92-driven signaling axis involving integrin activation of TGF-β in CSCs promotes enhanced tumorigenesis through induction of intratumoral immunosuppression.

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