AUTHOR=Dong Shuang-Shuang , Dong Dan-Dan , Yang Zhang-Fu , Zhu Gui-Qi , Gao Dong-Mei , Chen Jie , Zhao Yan , Liu Bin-Bin 

TITLE=Exosomal miR-3682-3p Suppresses Angiogenesis by Targeting ANGPT1 via the RAS-MEK1/2-ERK1/2 Pathway in Hepatocellular Carcinoma

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.633358

DOI=10.3389/fcell.2021.633358

ISSN=2296-634X

ABSTRACT=Abstract
Background
Angiogenesis is a crucial process in tumorigenesis and development. The role of exosomes derived from hepatocellular carcinoma cells in angiogenesis has not been clearly elucidated.
Methods and results
Exosomes were isolated from hepatocellular carcinoma cell lines (HCCLM3, MHCC97L and PLC/RFP/5) by ultracentrifugation and identified by nano transmission electron microscopy (TEM), NanoSight analysis and western blotting, respectively. In vitro and in vivo analyses showed that exosomes isolated from highly metastatic hepatocellular carcinoma (HCC) cells enhanced the migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) compared to exosomes derived from poorly metastatic hepatocellular carcinoma cells. In addition, microarray analysis of HCC-Exos was conducted to identify potential functional molecules, and miR-3682-3p expression was found to be significantly downregulated in exosomes isolated from highly metastatic hepatocellular carcinoma cells. By in vitro gain-of-function experiments, we found that HCC cells secreted exosomal miR-3682-3p, which negatively regulates ANGPT1, and this led to inhibition of RAS-MEK1/2-ERK1/2 signaling in endothelial cells and eventually impaired angiogenesis.
Conclusions
Our study elucidates that exosomal miR-3682-3p attenuates angiogenesis by targeting ANGPT1 through RAS-MEK1/2-ERK1/2 signaling and provides novel potential targets for liver cancer therapy.