Eukaryotic translation initiation factor 5A2 regulates the migration and invasion of hepatocellular carcinoma cells via pathways involving reactive oxygen species

// Rong-Rong Liu 1, * , Ya-Su Lv 1, * , Yue-Xiao Tang 1 , Yan-Fang Wang 1 , Xiao-Ling Chen 2 , Xiao-Xiao Zheng 1 , Shang-Zhi Xie 1 , Ying Cai 1 , Jun Yu 3 , Xian-Ning Zhang 1 1 Department of Cell Biology and Medical Genetics, Research Center for Molecular Medicine, National Education Base for Basic Medical Sciences, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, China 2 Department of Biological Chemistry, Zhejiang Chinese Medical University, Hangzhou, 310053, China 3 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Multi-Organ Transplantation of Ministry of Public Health, Hangzhou, 310003, China * These authors contributed equally to this work Correspondence to: Xian-Ning Zhang, e-mail: zhangxianing@zju.edu.cn Jun Yu, e-mail: Dr.yujun@gmail.com Keywords: eukaryotic translation initiation factor 5A2, reactive oxygen species, epithelial-mesenchymal transition, migration, hepatocellular carcinoma Received: September 24, 2015 Accepted: February 28, 2016 Published: March 23, 2016 ABSTRACT Eukaryotic translation initiation factor 5A2 ( eIF5A2 ) has been identified as a critical gene in tumor metastasis. Research has suggested that reactive oxygen species (ROS) serve as signaling molecules in cancer cell proliferation and migration. However, the mechanisms linking eIF5A2 and ROS are not fully understood. Here, we investigated the effects of ROS on the eIF5A2-induced epithelial-mesenchymal transition (EMT) and migration in six hepatocellular carcinoma (HCC) cell lines. Western hybridization, siRNA transfection, transwell migration assays, wound-healing assays, and immunofluorescence analysis were used. The protein levels of eIF5A2 in tumor and adjacent tissue samples from 90 HCC patients with detailed clinical, pathological, and clinical follow-up data were evaluated. Overexpression of eIF5A2 was found in cancerous tissues compared with adjacent tissues. We found that eIF5A2 overexpression in HCC was associated with reduced overall survival. Knockdown of eIF5A2 and intracellular reduction of ROS significantly suppressed the invasion and metastasis of HCC cells. Interestingly, N1-guanyl-1, 7-diaminoheptane (GC7) suppressed the intracellular ROS levels. After blocking the EMT, administration of GC7 or N-acetyl-L-cysteine did not reduce cell migration further. Based on the experimental data, we concluded that inhibition of eIF5A2 alters progression of the EMT to decrease the invasion and metastasis of HCC cells via ROS-related pathways.