School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Tianjin Medical University Cancer Institute and Hospital, Huanhu West Road, Tianjin 300060, China.
Exp Cell Res. 2018 Apr 1;365(1):12-23. doi: 10.1016/j.yexcr.2018.02.008. Epub 2018 Feb 14.
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.
胰腺导管腺癌（PDAC）是最致命的人类恶性肿瘤，因为其早期发生局部侵袭和远处转移。神经周围侵犯是胰腺腺癌的一个显著特征，是一个涉及不同信号通路的各种信号分子的多因素过程。神经胶质细胞系衍生的神经营养因子家族配体被报道参与胰腺癌的神经周围侵犯。Artemin 是神经胶质细胞系衍生的神经营养因子家族配体的一员。尽管 Artemin 先前已被证明可促进胰腺癌的侵袭性，但其机制仍知之甚少。在这项研究中，我们进行了分析以确定 Artemin 对调节肿瘤细胞转移潜力和侵袭活性的影响，并探讨了其在胰腺癌中的机制。我们表明，Artemin 和 CXCR4 在癌症组织中过度表达，并在广泛表达于胰腺癌细胞系中。我们观察到，Artemin 处理细胞中 ERK1/2 和 Akt 的激活导致 NF-κB 的核积累增加，从而诱导 CXCR4 的表达。通过调节 CXCR4 的表达，Artemin 可通过调节 SDF-1α/CXCR4 轴，功能性地促进胰腺癌细胞的迁移和侵袭。本研究表明，Artemin 通过激活 Akt 和 ERK1/2/NF-κB 信号通路诱导 CXCR4 表达，从而调节胰腺癌细胞的转移潜力和侵袭活性。Artemin 可能是治疗胰腺癌转移的有效和强效的治疗靶点，特别是在神经周围侵犯中。
