Exosomal miRNA-107 induces myeloid-derived suppressor cell expansion in gastric cancer
Received 22 December 2018
Accepted for publication 20 February 2019
Published 6 May 2019 Volume 2019:11 Pages 4023—4040
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Ahmet Emre Eskazan
WeiHong Ren,1,2 XuRan Zhang,2 WenBo Li,2 Qian Feng,2 HuiJie Feng,2 Yan Tong,2 Hao Rong,2 Wei Wang,2 Dai Zhang,2 ZhenQiang Zhang,3 ShiChun Tu,4 XiaoYan Zhu,1 QinXian Zhang1
1Department of Histology and Embryology, College of Basic Medicine, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 3Immunology Laboratory of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 4Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA, USA
Background: Myeloid-derived suppressor cells (MDSCs) promote immunosuppression in the tumor microenvironment, support tumor growth and survival, and may contribute to immunotherapy resistance. Recent studies showed that tumor-derived exosomes (TDEs) can induce MDSCs accumulation and expansion, the mechanisms of which are largely unknown.
Methods: The morphologies and sizes of the exosomes was observed by using a JEM-1400 transmission electron microscope. MicroRNA(miR)-107 and ARG1, DICER1, PTEN, PI3K, AKT, mTOR, and NF-kB mRNAs were quantified by quantitative reverse tanscription PCR. Dual-Luciferase Reports Assay were used to examine the expression of genes which was targeted by miR-107. The expression of proteins were analyzed by using western blot.
Results: MiR-107 was not only overexpressed in gastric cancer cells but also enriched in their secreted TDEs. Also, these miR-107 enriched TDEs could be taken up by HLA-DR-,CD33+,MDSCs, where miR-107 was able to target and suppress expression of DICER1 and PTEN genes. Dampened DICER1 expression supported expansion of MDSCs , while decreased PTEN led to activation of the PI3K pathway, resulting in increased ARG1 expression. Furthemore, gastric cancer-derived miR-107 TDEs, when dosed intravenously into mice, were also capable of inducing expansion of CD11b+,Gr1+/high ,MDSCs in mouse peripheral blood and altering expression of DICER1, PTEN, ARG1, and NOS2 in the MDSCs.
Conclusions: Our findings demonstrate for the first time that gastric cancer-secreted exosomes are able to deliver miR-107 to the host MDSCs where they induce their expansion and activition by targeting DICER1 and PTEN genes, thereby may provide novel cancer therapeutics target for gastric cancer.
Keywords: exosome, miRNA-107, myeloid-derived suppressor cell, arginase 1, gastric cancer
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