c-Src activation promotes nasopharyngeal carcinoma metastasis by inducing the epithelial-mesenchymal transition via PI3K/Akt signaling pathway: a new and promising target for NPC

// Liangru Ke 1, 2, * , Yanqun Xiang 1, 2, * , Xiang Guo 1, 2, * , Jinping Lu 4 , Weixiong Xia 1, 2 , Yahui Yu 1, 2 , Yongjian Peng 2 , Li Wang 2 , Gang Wang 2 , Yanfang Ye 3 , Jing Yang 1, 2 , Hu Liang 1, 2 , Tiebang Kang 2 , Xing Lv 1, 2 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 2 Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China 3 Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, China 4 Medical Research Center and Clinical Laboratory, Zhuhai Hospital, Jinan University, Zhuhai People’s Hospital, Zhuhai, China * These authors contributed equally to this work Correspondence to: Xing Lv, email: lvxing@sysucc.org.cn Tiebang Kang, email: kangtb@mail.sysu.edu.cn Keywords: nasopharyngeal carcinoma, metastasis, c-Src activation, therapy target, epithelial-mesenchymal transition Received: June 14, 2015 Accepted: March 18, 2016 Published: April 07, 2016 ABSTRACT Aberrant activation of cellular Src (c-Src), a non-receptor tyrosine kinase, could promote cancer progression through activating its downstream signaling pathways. However, the roles of c-Src and phosphorylated-Src (p-Src) in nasopharyngeal carcinoma (NPC) progression are rarely investigated. Herein, we have identified high c-Src concentrations in the serum of NPC patients with distant metastasis using high-throughput protein microarrays. Levels of c-Src in serum and p-Src in human primary NPC samples were unfavorable independent prognostic factors for cancer-specific survival, disease-free survival, and distant metastasis-free survival. Depletion or inactivation of c-Src in NPC cells using sgRNA with CRISPR/Cas9 system or PP2 decreased cell viability, colony formation, migration and invasion in vitro and metastasis in vivo . In contrast, these malignancies could be up-regulated by overexpressed c-Src in a NPC cell line with low-metastasis potential. Furthermore, p-Src was involved in promoting NPC cell metastasis by inducing the epithelial-mesenchymal transition (EMT) process via activating the PI3K/Akt pathway and cytoskeleton remodeling. The p-Src-induced EMT process could be retarded by PP2, which mediated by down-regulating the PI3K/Akt pathway. In conclusion, elevated levels of c-Src in serum and p-Src in primary NPC tissue correlated with poor outcomes of NPC patients. And aberrant activation of c-Src facilitated NPC cells with malignant potential, especially metastasis ability, which mediated by the PI3K/Akt pathway activation and sequentially induced the EMT process. These findings unveiled a promising approach for targeted therapy of advanced NPC.