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

Peng Gao; Dan Wang; Meiyue Liu; Siyuan Chen; Zhao Yang; Jie Zhang; Huan Wang; Yi Niu; Wei Wang; Jilong Yang; Guogui Sun

doi:10.1371/journal.pgen.1008592

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

PLoS Genet. 2020 Apr 28;16(4):e1008592. doi: 10.1371/journal.pgen.1008592. eCollection 2020 Apr.

Authors

Peng Gao^{1

2}, Dan Wang², Meiyue Liu², Siyuan Chen², Zhao Yang², Jie Zhang³, Huan Wang², Yi Niu², Wei Wang¹, Jilong Yang¹, Guogui Sun²

Affiliations

¹ Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
² Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan, China.
³ Department of Pathology, North China University of Science and Technology Affiliated People's Hospital, Tangshan, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement
Cell Proliferation / genetics
DNA Methylation*
Disease Progression
Esophageal Neoplasms / genetics
Esophageal Neoplasms / pathology*
Esophageal Squamous Cell Carcinoma / genetics
Esophageal Squamous Cell Carcinoma / pathology*
Exosomes / genetics*
Gene Expression Regulation, Neoplastic
Glycoside Hydrolases / metabolism*
Humans
Mice
MicroRNAs / genetics*
Neoplasm Metastasis / genetics
Serum / cytology
Signal Transduction*
Survival Rate
Vascular Endothelial Growth Factor A / metabolism*

Substances

MIRN652 microRNA, human
MicroRNAs
VEGFA protein, human
Vascular Endothelial Growth Factor A
Glycoside Hydrolases
poly ADP-ribose glycohydrolase

Grants and funding

This work was supported by the Young Top-Notch talent Project of Hebei province [No. JI2016(10), http://www.hebgcdy.com/], Talent Project of Hebei province (A201801005, http://rst.hebei.gov.cn/index.html), Academician Workstation Construction Special Project Of Tangshan People's Hospital (199A77119H, https://kjt.hebei.gov.cn/www/index_ssl/index.html), Natural Science Foundation of Outstanding Youth of Hebei Province (H2019105026, https://kjt.hebei.gov.cn/www/index_ssl/index.html), and Basic Research Cooperation Project of Beijing-Tianjin-Hebei [H2019105143,19JCZDJC64500(Z), https://kjt.hebei.gov.cn/www/index_ssl/index.html]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.