ZIP4 promotes non-small cell lung cancer metastasis by activating snail-N-cadherin signaling axis

Yuanyuan Jiang; Hanxiang Zhan; Yuqing Zhang; Jingxuan Yang; Mingyang Liu; Chao Xu; Xiao Fan; Junxia Zhang; Zhijun Zhou; Xiuhui Shi; Rajagopal Ramesh; Min Li

doi:10.1016/j.canlet.2021.08.025

ZIP4 promotes non-small cell lung cancer metastasis by activating snail-N-cadherin signaling axis

Cancer Lett. 2021 Aug 24:521:71-81. doi: 10.1016/j.canlet.2021.08.025. Online ahead of print.

Authors

Yuanyuan Jiang¹, Hanxiang Zhan², Yuqing Zhang³, Jingxuan Yang³, Mingyang Liu³, Chao Xu⁴, Xiao Fan⁵, Junxia Zhang⁶, Zhijun Zhou³, Xiuhui Shi³, Rajagopal Ramesh⁷, Min Li⁸

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shandong, China; Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
² Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
³ Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴ Department of Biostatistics and Epidemiology, Hudson College of Public Health, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
⁶ Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
⁷ Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁸ Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: Min-Li@ouhsc.edu.

PMID: 34450198
DOI: 10.1016/j.canlet.2021.08.025

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.

Keywords: Epithelial-mesenchymal transition; Metastasis; Non-small cell lung cancer; Snail; ZIP4.