Send to

Choose Destination
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

Pathology, Microbiology, and Immunology, University of South Carolina.
Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine.
Pathology Mircobiology and Immunology, University of South Carolina.
Pathology, University of South Carolina


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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center