Myeloid-derived suppressor cells (MDSCs) potently suppress the anti-tumor immune responses and also orchestrate the tumor microenvironment that favors tumor angiogenesis and metastasis. The molecular networks regulating the accumulation and functions of tumor-expanded MDSCs are largely unknown. In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors, as an essential player in regulating the accumulation and activity of MDSCs by targeting of phosphatase and tensin homolog (PTEN) and activation of the Akt pathway. TGF-β1 was found to be the main tumor-derived factor responsible for the upregulation of miR-494 in MDSCs. Expression of miR-494 not only enhanced CXCR4-mediated MDSC chemotaxis but also altered the intrinsic apoptotic/survival signal by targeting of PTEN, thus contributing to the accumulation of MDSCs in tumor tissues. Consequently, downregulation of PTEN resulted in increased activity of the Akt pathway and the subsequent upregulation of MMPs for facilitation of tumor cell invasion and metastasis. Knockdown of miR-494 significantly reversed the activity of MDSCs and inhibited the tumor growth and metastasis of 4T1 murine breast cancer in vivo. Collectively, our findings reveal that TGF-β1–induced miR-494 expression in MDSCs plays a critical role in the molecular events governing the accumulation and functions of tumor-expanded MDSCs and might be identified as a potential target in cancer therapy.

MicroRNAs are small non-coding RNA molecules that regulate gene expression by either translational inhibition or mRNA degradation. MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses, including TLR-triggered inflammatory response. Here we reported that the expression of microRNA-223 (miR-223) was significantly decreased in murine macrophages during activation by lipopolysaccharide (LPS) or poly (I∶C) stimulation. The inducible miR-223 down-regulation resulted in the activation of signal transducer and activator of transcription 3 (STAT3), which is directly targeted by miR-223, thus promoting the production of pro-inflammatory cytokines IL-6 and IL-1β, but not TNF-α. Interestingly, IL-6 was found to be a main factor in inducing the decrease in miR-223 expression after LPS stimulation, which formed a positive feedback loop to regulate IL-6 and IL-1β. Herein, our findings provide a new explanation characterizing the molecular mechanism responsible for the regulation of IL-6 production after TLR-triggered macrophage activation.

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A dietary deficiency of vitamin A is associated with cardiovascular abnormalities in avian and murine systems. Retinoic acid (RA) is the active metabolite of vitamin A and whether it directly regulates mammalian blood vessel formation has not been determined and is investigated herein. We used mice rendered RA-deficient via targeted deletion of retinaldehyde dehydrogenase 2 (Raldh2-/-), the enzyme required to produce active RA in the embryo. Histological examination at E8.0-8.5, prior to cardiac function and systemic blood circulation, revealed that capillary plexi formed in Raldh2-/- yolk sacs and embryos, but were dilated, and not appropriately remodeled or patterned. Raldh2-/- endothelial cells exhibited significantly increased expression of phosphohistone 3 and decreased expression of p21 and p27, suggesting that RA is required to control endothelial cell cycle progression during early vascular development. Uncontrolled endothelial cell growth, in Raldh2-/- mutants, was associated with decreased endothelial cell maturation, disrupted vascular plexus remodeling and lack of later stages of vessel assembly, including mural cell differentiation. Maternally administrated RA restored endothelial cell cycle control and vascular patterning. Thus, these data indicate that RA plays a crucial role in mammalian vascular development; it is required to control endothelial cell proliferation and vascular remodeling during vasculogenesis.