Tumor-secreted GRP78 facilitates the migration of macrophages into tumors by promoting cytoskeleton remodeling

Abstract

Glucose-regulated protein 78 (GRP78), an important molecular chaperone in the endoplasmic reticulum, is often over-expressed in the central region of advanced tumor and acts as a promoter of tumor progression. As main immune cells in the tumor microenvironment, infiltration of abundant macrophages into advanced tumor further facilitates growth of tumor. Although has potential association between GRP78 and infiltration of macrophages, its underlying mechanisms are poorly understood. Here, we report that secreted GRP78 facilitates recruitment of macrophages into tumors both in vitro and in vivo. Further studies reveal that secreted GRP78 transports into macrophages and bound to intracellular Ca²⁺, which lead to uneven distribution of Ca²⁺ and subsequent polarization of macrophages. The polarization of macrophages activates expression of microRNA-200b-3p. By directly targeting RhoGDI, miR-200b-3p stimulates the activity of RhoGTPase and ultimately leads to the distribution of GTP-Rac1 and GTP-Cdc42 in front protrusion and GTP-RhoA in rear contraction, which further results in migration of macrophages in a certain direction. Our results reveal a novel function of GRP78 to promote the recruitment of macrophages to tumor and provide a potential therapeutic target for malignancies.

Keywords: Ca(2+); Cytoskeleton remodeling; Directional migration; Macrophages; Tumor-secreted GRP78.