title: 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.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Lihua
authors.initials: L
authors.lastname: Lai
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Chen
authors.forename: Yinjing
authors.initials: Y
authors.lastname: Song
authors.forename: Sheng
authors.initials: S
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Ma
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.forename: Hai
authors.initials: H
authors.lastname: Yu
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung; D002449:Cell Aggregation / Q000276:immunology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000378:metabolism* / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology
chemical_list: C514936:CXCR4 protein, mouse; D035683:MicroRNAs; C550178:Mirn494 microRNA, mouse; D019718:Receptors, CXCR4; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse