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

• Published in: Molecular therapy. Nucleic acids Vol. 22; pp. 615 - 626
• Main Authors: Li, Ping, Luo, Xingdong, Xie, Yue, Li, Pengfei, Hu, Fangyong, Chu, Junfeng, Chen, Xiaojun, Song, Wenbo, Wang, Ali, Tian, Guangyu, Gu, Xiang
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 04.12.2020; American Society of Gene & Cell Therapy; Elsevier
• Subjects: CXXC finger protein 4; extracellular vesicles; gastric cancer; immune escape; microRNA-675-3p; Original; programmed cell death 1 ligand 1; immune escape; extracellular vesicles; gastric cancer; microRNA-675-3p; programmed cell death 1 ligand 1; CXXC finger protein 4
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2020.08.020

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. [Display omitted] Gastric cancer-derived extracellular vesicles enriched with miR-675-3p inhibit the target gene CXXC4 and elevate PD-L1 expression through the MAPK signaling pathway, thus stimulating the immune escape and cisplatin resistance of gastric cancer cells.