MicroRNA-9 Regulates the Differentiation and Function of Myeloid-Derived Suppressor Cells via Targeting Runx1

Abstract

Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-associated immunosuppression, thus affecting effective immunotherapies for cancers. However, the molecular mechanisms involved in regulating the differentiation and function of MDSCs remain largely unclear. In this study, we found that inhibition of microRNA (miR)-9 promoted the differentiation of MDSCs with significantly reduced immunosuppressive function whereas overexpression of miR-9 markedly enhanced the function of MDSCs. Notably, knockdown of miR-9 significantly impaired the activity of MDSCs and inhibited the tumor growth of Lewis lung carcinoma in mice. Moreover, miR-9 regulated MDSCs differentiation by targeting the runt-related transcription factor 1, an essential transcription factor in regulating MDSC differentiation and function. Furthermore, the CREB was found to regulate miR-9 expression in MDSCs. Taken together, our findings have identified a critical role of miR-9 in regulating the differentiation and function of MDSCs.

MicroRNA‐9 promotes cell proliferation by regulating RUNX1 expression in human megakaryocyte development

“…We read with interest the article by Tian et al, 1 describing the role of MicroRNA-9 (miR-9) in the regulation of myeloid-derived suppressor cell (MDSC) differentiation and function by targeting the runt-related transcription factor 1 (Runx1). This finding has revealed posttranscriptional regulation of Runx1 by miR-9.…”

Regulation of Gene Expression by β-Glucans

“…A microRNA microarray in Whole β-Glucan Particles (WGP)-treated MDSCs isolated from the spleen of Lewis lung carcinoma bearing mice identified 61 miRNAs that were downregulated whereas 40 miRNAs were upregulated (Tian et al, 2015). Specifically, the authors identified miR-9 as an important regulator of Runx1 (runt-related transcription factor) as a direct, bona fide target of miR-9 (verified by 3'UTR luciferase reporter assay in HEK-293T cells).…”

“…These data demonstrated that IL-1 and IFN-γ differentially regulate the β-glucan-induced Th responses in human DCs. Splenic MDSC from 100 ug mL −1 for 24 h; whole (Tian et al, 2015) miRNA microarray assay downregulated miRNAs tumor-bearing mice β-glucan particles from GEO accession number -focused on mmu-miR-9 S. Cerevisiae GSE67578; Identified Runx1, a CREB mRNA and protein transcription factor involved in differentiation of MDSCs, as a direct, bona fide target of miR-9. CREB, transcription factor, suppressed miR-9 transcription.…”

“…Treatment of murine Myeloid-Derived Suppressor Cells (MDSCs) with whole β-glucan particles was shown to increase the expression of Runx1, a transcription factor that induces differentiation in Myeloid-Derived Suppressor Cells (MDSC) and mmumiR-181d in M-MDSCs (downregulated in G-MDSCs) (Tian et al, 2015). These authors did not examine the function of miR-181d and a search in PubMed revealed no studies examining miR-181d in MDSCs.…”

“…These results support the conclusion that through the Dectin-1 receptor, CREB directly regulates miR-9 expression in response to β-glucan. The downregulation of miR-9 results in an increase in Runx1 allows for differentiation, decreased immunosuppressive function and reduced tumor growth (Tian et al, 2015).…”