Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-κB signaling and is associated with metastasis and poor prognosis in gastric cancer patients

// Jian Li 1, 2, 3, * , Zhijuan Deng 1, * , Zhu Wang 4 , Dong Wang 5 , Longjuan Zhang 1 , Qiao Su 8 , Yingrong Lai 6 , Bin Li 6 , Zexing Luo 1 , Xu Chen 1, 7 , Yu Chen 1 , Xiaohui Huang 1 , Jieyi Ma 1 , Wenjian Wang 1 , Jiong Bi 1 , Xinyuan Guan 2 1 Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China 2 State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China 3 Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China 4 Department of Medical Ultrasonics Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China 5 Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China 6 Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China 7 School of Public Health, Sun Yat-Sen University, Guangzhou 510074, China 8 Animal Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China * These authors have contributed equally to this work Correspondence to: Jiong Bi, e-mail: bijiong2000@hotmail.com Keywords: zipper-interacting protein kinase, epithelial-mesenchymal transition, gastric cancer, metastasis, AKT/IκB/NF-κB pathway Received: September 09, 2014      Accepted: January 23, 2015      Published: March 21, 2015 ABSTRACT Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family. ZIPK has been characterized as a tumor suppressor in various tumors, including gastric cancer. On the other hand, ZIPK also promotes cell survival. In this study, both in vitro and in vivo assays indicated that ZIPK promoted cell growth, proliferation, migration, invasion, tumor formation and metastasis in nude mice. ZIPK induced epithelial-mesenchymal transition (EMT) with increasing expression of β-catenin, mesenchymal markers, Snail and Slug, and with decreasing expression of E-cadherin. Furthermore, ZIPK activated the AKT/IκB/NF-κB pathway, which can promote EMT and metastasis. Additionally, ZIPK expression was detected in human primary gastric cancer and their matched metastatic lymph node samples by immunohistochemistry. Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion. Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease-specific survival. Taken together, our study reveals that ZIPK is a pro-oncogenic factor, which promotes cancer metastasis.