Exosomal CLIC1 released by CLL promotes HUVECs angiogenesis by regulating ITGβ1-MAPK/ERK axis

摘要

Accumulating evidences have suggested that exosomes are closely associated with tumor progression by affecting cell-cell communication. Here, we aimed to investigate the roles and regulatory mechanism of exosomes released from chronic lymphocytic leukemia (CLL). The expression levels of genes and proteins in cells and exosomes were examined by quantitative real-time PCR and Western blotting, respectively. MEC-1 cell-derived exosomes were obtained and co-cultured with human umbilical vein endothelial cells (HUVECs), then the capabilities of cell proliferation, metastasis and angiogenesis of HUVECs were measured by CCK-8, wound healing, transwell and tube formation assay, respectively. Chloride intracellular channel 1 (CLIC1) was significantly increased in CLL patients and markedly enriched in exosomes secreted by CLL cells. Exosomal CLIC1 secreted from MEC-1 cells were successfully transferred into HUVECs and significantly promoted the phenotypes of proliferation, metastasis and angiogenesis of HUVECs. Mechanically, exosomal CLIC1 secreted from MEC-1 cells obviously activated MAPK/ERK signaling through upregulating integrin β1 (ITGβ1) expression in HUVECs. Furthermore, rescue experiments revealed that either silencing ITGβ1 or PD98059 treatment obviously reversed the regulatory effects of exosomal CLIC1 secreted from MEC-1 cells in HUVECs. In conclusion, CLL cell-derived exosomes accelerated HUVECs metastasis and angiogenesis through transferring CLIC1 to regulate ITGβ1-MAPK/ERK signaling, indicating that CLIC1 may be a therapeutic target of CLL exosomes in the tumor microenvironment.