Previous studies have shown that endoplasmic reticulum (ER) stress serves an important role in shaping the immunosuppressive microenvironment by modulating resident immune cells. However, the communication between ER-stressed tumor cells and immune cells is not fully understood. Exosomes have been reported to play a vital role in intercellular communication. Therefore, in order to investigate the role of ER stress-related exosomes in liver cancer cells mediated macrophage function remodeling, immunohistochemical analysis, western-blotting immunofluorescence and cytokine bead array analyses were performed. The results demonstrated that glucose-regulated protein 78 (GRP78) expression was upregulated in human liver cancer tissue. Moreover, 69.09% of GRP78-positive liver cancer tissues possessed macrophages expressing CD68+ (r=0.55; P<0.001). In addition to these CD68+ macrophages, interleukin (IL)-10 and IL-6 expression levels were increased in liver cancer tissues. It was also demonstrated that exosomes released by ER-stressed HepG2 cells significantly enhanced the expression levels of several cytokines, including IL-6, monocyte chemotactic protein-1, IL-10 and tumor necrosis factor-α in macrophages. Furthermore, incubation of cells with ER stress-associated exosomes resulted inactivation of the Janus kinase 2/STAT3 pathway, and inhibition of STAT3 using S3I-201 in RAW264.7 cells significantly reduced cytokine production. Collectively, the present study identified a novel function of ER stress-associated exosomes in mediating macrophage cytokine secretion in the liver cancer microenvironment, and also indicated the potential of treating liver cancer via an ER stress-exosomal-STAT3 pathway.
Keywords: endoplasmic reticulum stress; exosome; inflammation; liver cancer; macrophage.
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