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Pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor because of the early onset of local invasion and distant metastasis. Perineural invasion is a prominent characteristic of pancreatic adenocarcinoma, which is a multifactorial process that involves various signaling molecules from different signaling pathways. The glial cell line-derived neurotrophic factor family of ligands was reported to be involved in perineural invasion in pancreatic cancer. Artemin is one member of the glial cell line-derived neurotrophic factor family of ligands. Although Artemin has previously been demonstrated to promote invasiveness of pancreatic cancer, the mechanisms remain poorly understood. In this study, we performed an analysis to determine the effects of Artemin on modulating tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. We indicated that Artemin and CXCR4 were overexpressed in cancer tissues and widely expressed in pancreatic cancer cell lines. We observed that activation of ERK1/2 and Akt in Artemin-treated cells led to enhanced nuclear accumulation of NF-κB, which then induced CXCR4 expression. Through regulation of the expression of CXCR4, Artemin functionally promoted the migration and invasion in pancreatic cancer cells. The present study indicated that Artemin induced CXCR4 expression by activating Akt and ERK 1/2/NF-κB signaling, thereby modulating tumor cell metastatic potential and invasion activity in pancreatic cancer by regulating SDF-1α/CXCR4 axis. Artemin might be an effective and potent therapeutic target for pancreatic cancer metastasis, especially in perineural invasion.Artemin regulates CXCR4 expression to induce migration and invasion in pancreatic cancer cells through activation of NF-κB signaling.Artemin activates Akt and ERK, which cooperatively mediates activation of NF-κB and subsequent CXCR4 up-regulation.Artemin induces an increase in migration and invasion potential in pancreatic cancer cell by regulating Akt and ERK1/2/NF-κB/CXCR4 signaling.