DNA methylation-mediated repression of exosomal miR-652-5p expression promotes oesophageal squamous cell carcinoma aggressiveness by targeting PARG and VEGF pathways

Author summary This study confirmed that miR-652-5p underexpression was a result of the hypermethylated promotor, which regulated OSCC development by targeting PARG and VEGF. Serum miR-652-5p might be used as a potential tumour marker to predict the OS of OSCC patients. The miR-652-5p gene may be a suppressor gene in OSCC, which serves as a potential therapeutic target for OSCC. Exosomal microRNAs (miRNAs) have been recently shown to play vital regulatory and communication roles in cancers. In this study, we showed that the expression levels of miR-652-5p in tumour tissues and serum samples of oesophageal squamous cell carcinoma (OSCC) patients were lower compared to non-tumorous tissues and serum samples from healthy subjects, respectively. Decreased expression of miR-652-5p was correlated with TNM stages, lymph node metastasis, and short overall survival (OS). More frequent CpG sites hypermethylation in the upstream of miR-652-5p was found in OSCC tissues compared to adjacent normal tissues. Subsequently, miR-652-5p downregulation promoted the proliferation and metastasis of OSCC, and regulated cell cycle both in cells and in vivo. The dual-luciferase reporter assay confirmed that poly (ADP-ribose) glycohydrolase (PARG) and vascular endothelial growth factor A (VEGFA) were the direct targets of miR-652-5p. Moreover, the delivery of miR-652-5p agomir suppressed tumour growth and metastasis, and inhibited the protein expressions of PARG and VEGFA in nude mice. Taken together, our findings provide novel insight into the molecular mechanism underlying OSCC pathogenesis.