CCL18 promotes epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells in pancreatic ductal adenocarcinoma

Abstract

CCL18 is a chemokine that is primarily expressed in monocytes, macrophages and immature dendritic cells and plays a crucial role in immune and inflammation responses. Recently, CCL18 was found to play pivotal roles in the development of several kinds of cancers, but its expression status and role during the tumorigenesis of pancreatic cancer remain unknown. In this study, we performed immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) to evaluate the expression of CCL18 in human pancreatic ductal adenocarcinoma (PDAC) tissues and preoperative serum, respectively. The results showed that both cancer epithelial cells and mesenchymal macrophages in PDAC tissues positively expressed CCL18. Serum CCL18 levels were significantly higher in patients with PDAC in comparison to healthy controls. The expression of CCL18 in both cancer epithelial cells and mesenchymal cells was correlated with lymph node metastasis, histopathological grading and overall survival in 62 PDAC patients. In vitro assays showed that the gene and protein expression of CCL18 from U937 and THP-1 cell- derived macrophages were significantly higher than that from unstimulated U937 cells and THP-1 cells. In contrast, pancreatic cancer cell lines showed little to no CCL18 expression even after IL4 stimulation. Intriguingly, pancreatic cancer cell lines expressed the potential CCL18 receptors PITPNM3, CCR6 and GPR3. Furthermore, treatment with recombinant human CCL18 promoted the migration and invasion of pancreatic cancer cells, but had no effect on cell proliferation. Consistent with these results, CCL18 induced the expression of the epithelial-mesenchymal transition (EMT) related gene SNAIL1. Our findings suggest that the serum level of CCL18 is a potential biomarker for the diagnosis and prognosis of PDAC, and that the combined functions of CCL18 in mesenchymal and cancer cells might accelerate the progression of PDAC by promoting the epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells.