Heat shock protein A4 controls cell migration and gastric ulcer healing.

Abstract

Heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, regulates the immune response in the gut. Here, we assessed the involvement of HSPA4 in gastric ulcer healing by using fibroblasts from wild-type and HSPA4-deficient mice, a murine gastric ulcer model, and samples from 65 patients with gastric cancer. HSPA4 expression was inversely correlated with gastric ulcer healing following endoscopic resection of gastric cancer. In the human gastric mucosa, the expression of HSPA4 was inversely correlated with the expression of stromal cell-derived factor 1 (SDF-1), its cognate receptor CXC chemokine receptor 4 (CXCR4), the stromal cell marker vimentin, and the epithelial-mesenchymal transition regulator Twist. HSPA4 was overexpressed in stromal cells as well as in human gastric cancer cells. HSPA4 deficiency increased the expression of SDF-1 and CXCR4, as well as the number of fibroblast-specific protein 1-positive cells, leading to accelerated ulcer healing in the murine gastric ulcer model. Deletion of HSPA4 promoted cell migration in mouse fibroblasts through increased expression of SDF-1 and Twist. HSPA4 regulates the expression of SDF-1 and Twist in fibroblasts, thereby controlling gastric ulcer healing.