Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-kB signaling and is associated with metastasis and poor prognosis in gastric cancer patients
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Jian Li1,2,3,*, Zhijuan Deng1,*, Zhu Wang4, Dong Wang5, Longjuan Zhang1, Qiao Su8, Yingrong Lai6, Bin Li6, Zexing Luo1, Xu Chen1,7, Yu Chen1, Xiaohui Huang1, Jieyi Ma1, Wenjian Wang1, Jiong Bi1, Xinyuan Guan2
1Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
2State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
3Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
4Department of Medical Ultrasonics Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
5Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
6Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
7School of Public Health, Sun Yat-Sen University, Guangzhou 510074, China
8Animal Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
*These authors have contributed equally to this work
Jiong Bi, e-mail: [email protected]
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
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.
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