Non-small cell lung cancer (NSCLC) is one of the most critical health problems worldwide, with high incidence and poor survival rate. A zinc importer ZIP4 has been implicated in the process of tumor growth and metastasis of many cancers. However, its exact role and the underlying mechanism in NSCLC remains to be elucidated. In the present study, we found that human ZIP4 was substantially overexpressed in NSCLC tissues and was correlated with poor overall survival (OS) and progression-free survival (PFS). Overexpression of ZIP4 promoted cell migration, invasion and metastasis both in vitro and in a mouse lung metastasis model. Silencing of ZIP4 attenuated migration, invasion and metastasis. Mechanistically, overexpression of ZIP4 increased the expression of Snail, Slug and N-cadherin while genetic inactivation of ZIP4 downregulated the expression of above-mentioned genes. Further analysis showed that transcriptional factor Snail which modulates N-cadherin was involved in the process of ZIP4-mediated NSCLC migration and invasion. We also demonstrated that ZIP4 positively correlates with the levels of Snail, Slug and N-cadherin in mice lung metastasis tumors. Together, these results suggest that ZIP4 acts as an important regulator of Snail-N-cadherin signaling axis in promoting NSCLC progression and may serve as a novel predictive marker and therapeutic target in NSCLC.

非小细胞肺癌（NSCLC）是世界范围内最严重的健康问题之一，发病率高，存活率低。锌输入体 ZIP4 与许多癌症的肿瘤生长和转移过程有关。然而，其在非小细胞肺癌中的确切作用和潜在机制仍有待阐明。在本研究中，我们发现人 ZIP4 在 NSCLC 组织中大量过度表达，并且与较差的总生存期 (OS) 和无进展生存期 (PFS) 相关。ZIP4的过表达促进了体外细胞迁移、侵袭和转移并在小鼠肺转移模型中。ZIP4 的沉默减弱了迁移、侵袭和转移。从机制上讲，ZIP4 的过表达增加了 Snail、Slug 和 N-cadherin 的表达，而 ZIP4 的遗传失活则下调了上述基因的表达。进一步分析表明，调节N-cadherin的转录因子Snail参与了ZIP4介导的NSCLC迁移和侵袭过程。我们还证明 ZIP4 与小鼠肺转移肿瘤中 Snail、Slug 和 N-钙粘蛋白的水平呈正相关。总之，这些结果表明 ZIP4 是 Snail-N-cadherin 信号轴的重要调节因子，可促进 NSCLC 进展，并可作为 NSCLC 的新型预测标志物和治疗靶点。