MicroRNA-494 Is Required for the Accumulation and Functions of Tumor-Expanded Myeloid-Derived Suppressor Cells via Targeting of PTEN

Abstract

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.

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

“…In addition, miR-494 enhances myocyte survival by targeting PTEN, ROCK1, and CAMKIId and protects against ischemia/reperfusion-induced cardiac injury (29). miR-494 is also an essential player in regulating the accumulation and activity of myeloidderived suppressor cells by targeting PTEN and activation of the Akt pathway (25). We confirmed a direct connection of PED S104G overexpression and down-regulation of miR-494.…”

“…It has recently been shown that miR-494 has an important role in tumor progression in myeloid-derived suppressor cells by targeting phosphatase and tensin homolog (PTEN) (25). As a result, we wondered if miR-494 could also have a role in tumorigenicity of NSCLC.…”

Distinct MicroRNA Expression Profile and Targeted Biological Pathways in Functional Myeloid-derived Suppressor Cells Induced by Δ9-Tetrahydrocannabinol in Vivo

“…Further, miR-223 was found to negatively regulate progenitor proliferation, granulocyte differentiation, and activation in a MEF2C-dependent manner (60). miR-494 expression induced by tumor-derived TGF-␤1 was shown to play a critical role in the regulation of accumulation and function of tumor-expanded MDSCs by specifically targeting PTEN (61). miR-17-5p and miR-20a could decrease the expression of reactive oxygen species and suppressive function of tumor-induced MDSCs by targeting Stat3 (62).…”

MicroRNA-92a Negatively Regulates Toll-like Receptor (TLR)-triggered Inflammatory Response in Macrophages by Targeting MKK4 Kinase

“…A total of 1 ϫ 10 4 HEK-293 cells were seeded onto 96-well plates and incubated overnight. jetSI-ENDO transfection reagents (Polyplus-transfection, Illkirch, France) were used for the cotransfection of plasmids and RNAs as we described previously (44). Thioglycollate-elicited mouse peritoneal macrophages were prepared and cultured as described previously (45).…”