The Endoplasmic Reticulum-Stressed Head and Neck Squamous Cell Carcinoma Cells Induced Exosomal miR-424-5p Inhibits Angiogenesis and Migration of Humanumbilical Vein Endothelial Cells Through LAMC1-Mediated Wnt/β-Catenin Signaling Pathway

Abstract

Under endoplasmic reticulum (ER) stress, tumor plays multifaceted roles in endothelial cell dysfunction through secreting exosomal miRNAs. However, for the head and neck squamous cell carcinoma (HNSCC), it is still unclear about the impact of ER-stressed HNSCC cell derived exosomes on vascular endothelial cells. To address this gap, herein, systemic research was conducted including isolation and characterization of ER-stressed HNSCC cell (HN4 cell line as an in vitro model) derived exosomes, identification of regulatory exosomal miRNAs, target exploration and downstream signaling pathway investigation of exosomal miRNAs in human umbilical vein endothelial cell (HUVEC). ER-stressed HN4 cell-derived exosomes inhibited angiogenesis and migration of HUVEC cells in vitro . Furthermore, RNA-seq analysis demonstrated that miR-424-5p was highly upregulated in ER-stressed HN4 cell-derived exosomes. Through matrigel tube formation and transwell assays of HUVEC cells, miR-424-5p displayed great capabilities on inhibiting angiogenesis and migration. Finally, based on western blot and luciferase reporter, it was demonstrated that LAMC1 is the target of miR-424-5p which could inhibit the angiogenesis and migration of HUVEC cells by repressing the LAMC1-mediated Wnt/β-catenin signaling pathway. ER-stressed HNSCC cell-induced exosomal miR-424-5p inhibits angiogenesis and migration of HUVEC cells through LAMC1-mediated Wnt/β-catenin signaling pathway. This study offers a new insight for understanding the complicated mechanism behind ER-stress induced anti-angiogenesis of HNSCC.