ZIP4 promotes non-small cell lung cancer metastasis by activating snail-N-cadherin signaling axis. (28th November 2021)

• Record Type: Journal Article
• Authors: Jiang, Yuanyuan; Zhan, Hanxiang; Zhang, Yuqing; Yang, Jingxuan; Liu, Mingyang; Xu, Chao; Fan, Xiao; Zhang, Junxia; Zhou, Zhijun; Shi, Xiuhui; Ramesh, Rajagopal; Li, Min
• Is Part Of: Cancer letters. Volume 521(2021)
• Page Start: 71
• Page End: 81
• Publication Date: 2021-11-28
• Subjects: ZIP4 -- Non-small cell lung cancer -- Snail -- Epithelial-mesenchymal transition -- Metastasis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.08.025
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Zinc transporters are differentially expressed in NSCLC; ZIP4 is substantially overexpressed in lung squamous carcinoma and adenocarcinoma and predicts survival in NSCLC patients. ZIP4 promotes NSCLC progression and metastasis through a zinc dependent transcriptional factor snail pathway. N-cadherin is a downstream EMT plasticity mediator of ZIP4/snail signaling axis promoting NSCLC metastasis. This novel ZIP4-Snail signaling cascade may serve as a novel predictive marker and therapeutic target in NSCLC.