Deregulated expression of chemokines in tumor microenvironment contributes to tumor metastasis by targeting distinct cells. Epithelial-derived neutrophil-activating peptide-78 (ENA78/CXCL5) is upregulated in many cancers and involved in tumor progression. The role and underlying mechanism of CXCL5 in gastric cancer (GC) metastasis remain unclear. In this study, we reported that the expression of CXCL5 was elevated in tumor tissues and positively associated with lymphatic metastasis and tumor differentiation. Stimulation by recombinant human CXCL5 (rhCXCL5) induced epithelial-mesenchymal transition (EMT) in GC cells through the activation of ERK pathway, which enhanced their migration and invasion abilities. The culture supernatant from tumor tissues also enhanced the migration and invasion abilities of GC cells, however, this effect was reversed by pre-treatment with CXCL5 neutralizing antibody. Further studies showed that rhCXCL5 could induce the expression of IL-6 and IL-23 in neutrophils through the activation of ERK and p38 signaling pathways, which in turn facilitated GC cell migration and invasion. The culture supernatant from tumor tissues showed similar effects on neutrophils in a CXCL5-dependent manner. Blockade of IL-6 and IL-23 with neutralizing antibodies reversed the induction of EMT and the increased migration and invasion abilities in GC cells by CXCL5-activated neutrophils. Moreover, CXCL5 activated neutrophils could promote gastric cancer metastasis in vivo. Taken together, our results indicate that CXCL5 acts on gastric cancer cells to induce EMT and mediates pro-tumor activation of neutrophils, which synergistically promotes the metastatic ability of GC cells.

肿瘤微环境中趋化因子的失调表达通过靶向不同的细胞促进肿瘤转移。上皮衍生的中性粒细胞激活肽 78 (ENA78/CXCL5) 在许多癌症中上调并参与肿瘤进展。CXCL5 在胃癌 (GC) 转移中的作用和潜在机制仍不清楚。在本研究中，我们报道了 CXCL5 在肿瘤组织中的表达升高，并且与淋巴转移和肿瘤分化呈正相关。重组人 CXCL5 (rhCXCL5) 的刺激通过激活 ERK 通路诱导 GC 细胞中的上皮间质转化 (EMT)，从而增强其迁移和侵袭能力。来自肿瘤组织的培养上清液也增强了 GC 细胞的迁移和侵袭能力，然而，用 CXCL5 中和抗体预处理可以逆转这种作用。进一步的研究表明，rhCXCL5 可通过激活 ERK 和 p38 信号通路诱导中性粒细胞中 IL-6 和 IL-23 的表达，进而促进 GC 细胞迁移和侵袭。来自肿瘤组织的培养上清液以 CXCL5 依赖性方式对中性粒细胞显示出类似的作用。用中和抗体阻断 IL-6 和 IL-23 可逆转 EMT 的诱导以及 CXCL5 激活的中性粒细胞在 GC 细胞中增加的迁移和侵袭能力。此外，CXCL5激活的中性粒细胞可以促进胃癌体内转移。总之，我们的结果表明 CXCL5 作用于胃癌细胞以诱导 EMT 并介导嗜中性粒细胞的促肿瘤激活，