GC-Derived EVs Enriched with MicroRNA-675-3p Contribute to the MAPK/PD-L1-Mediated Tumor Immune Escape by Targeting CXXC4

Molecular Therapy: Nucleic Acids

Fangyong Hu¹  Yue Xie²  Xiaojun Chen³  Pengfei Li³  Guangyu Tian³  Xingdong Luo³  Ali Wang⁴  Ping Li⁴  Xiang Gu⁴  Wenbo Song⁵  Junfeng Chu⁶ 

[1] Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University, 68167 Mannheim, Germany;;Department of General Surgery, Huaian Tumor Hospital &Huaian Hospital of Huaian City, Huaian 223200, P.R. China;;Department of Central Laboratory, Huaian Tumor Hospital &Department of General Surgery, Gaoyou Traditional Chinese Medicine Hospital, Gaoyou 225600, P.R. China;;Department of General Surgery, Huaian Tumor Hospital &

关键词: gastric cancer;    immune escape;    extracellular vesicles;    microRNA-675-3p;    CXXC finger protein 4;    programmed cell death 1 ligand 1;   

DOI  :  

来源: DOAJ

【 摘 要 】

MicroRNAs (miRNAs) delivered by gastric cancer (GC)-secreted extracellular vesicles (GC-EVs) are associated with the immune escape in GC. Microarray analysis based on the GEO: GSE112369 dataset identified the presence of poorly expressed CXXC finger protein 4 (CXXC4) in GC, which was validated in clinical samples of GC patients. Moreover, prediction based on TargetScan analysis demonstrated the putative miR-675-3p binding site in the 3′ UTR region of CXXC4. Thereby, our study aims to determine the role of GC-EV-encapsulated miR-675-3p in GC. First, CXXC4 was found to be negatively correlated with programmed cell death 1 ligand 1 (PD-L1). The effects of mitogen-activated protein kinase (MAPK) signaling on GC were evaluated using activator of the MAPK pathway. The overexpression of CXXC4 led to a downregulated MAPK signaling pathway, thus decreasing PD-L1 expression to augment the proliferation and activation of T cells co-cultured with GC HGC-27 cells. GC-EV-encapsulated miR-675-3p negatively regulated the expression of its target gene CXXC4. GC-EV-encapsulated miR-675-3p increased PD-L1 expression to stimulate the immune escape in vitro and EV-encapsulated miR-675-3p accelerated cisplatin resistance in vivo. Collectively, the aforementioned findings present a mechanism in which EV-mediated miR-675-3p upregulates PD-L1 expression, promoting immune escape in GC.

【 授权许可】

Unknown