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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.

The electrochemistry of anthraquinone-2,6-disulfonate (2,6-AQDS) at glassy carbon (GC), hydrogenated glassy carbon (HGC), the basal plane of highly oriented pyrolytic graphite (HOPG), and boron-doped diamond was investigated by cyclic voltammetry and chronocoulometry. Quantitative determination of the surface coverage and qualitative assessment of the physisorption strength of 2,6-AQDS adsorption on each of these electrodes were done. The diamond and HGC surfaces are nonpolar and relatively oxygen-free, with the surface carbon atoms terminated by hydrogen. The polar 2,6-AQDS does not adsorb on these surfaces, and the electrolysis proceeds by a diffusion-controlled reaction. Conversely, the GC and HOPG surfaces are polar, with the exposed defect sites terminated by carbon-oxygen functionalities. 2,6-AQDS strongly physisorbs on both of these surfaces at near monolayer or greater coverages, such that the electrolysis proceeds through a surface-confined state. Less than 40% of the initial surface coverage can be removed by rinsing and solution replacement, reflective of strong physisorption. The results show the important role of the surface carbon-oxygen functionalities in promoting strong dipole-dipole and ion-dipole interactions with polar and ionic molecules such as 2,6-AQDS. The results also support the theory that diamond electrodes may be less subject to fouling by polar adsorbates, as compared to GC, leading to improved response stability in electroanalytical measurements. The relationship between the 2,6-AQDS surface coverage, the double-layer capacitance, and the heterogeneous electron-transfer rate constant for Fe(CN)(6)(3)(-)(/4)(-) for these four carbon electrodes is presented.

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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