ATG4A promotes tumor metastasis by inducing the epithelial-mesenchymal transition and stem-like properties in gastric cells

// Shi-Wei Yang 1,2 , Yi-Fang Ping 2,3 , Yu-Xing Jiang 1 , Xiao Luo 1 , Xia Zhang 2,3 , Xiu-Wu Bian 2,3 and Pei-Wu Yu 1 1 Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China 2 Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Third Military Medical University, Chongqing, China 3 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China Correspondence to: Xiu-Wu Bian, email: // Pei-Wu Yu, email: // Keywords : ATG4A, epithelial-mesenchymal transition, gastric cancer, metastasis, tumor stem cell, Pathology Section Received : October 11, 2015 Accepted : May 14, 2016 Published : June 04, 2016 Abstract The metastasis of tumor cells to distant organs is an ominous feature of gastric cancer. However, the molecular mechanisms underlying the invasion and metastasis of gastric cancer cells remain elusive. In this study, we found that the expression of ATG4A, an autophagy-regulating molecule, was significantly increased in gastric cancer tissues and was significantlycorrelated with the gastric cancer differentiation degree, tumor invasion and lymph node metastasis. ATG4A over-expression significantly promoted gastric cancer cell migration and invasion in vitro and metastasis in vivo , as well as promoted gastric cancer cell stem-like properties and the epithelial-mesenchymal transition (EMT) phenotype. By contrast, ATG4A knockdown inhibited the migration, invasion and metastasis of cancer cells, as well as the stem-like properties and EMT phenotype. Mechanistically, ATG4A promotes gastric cancer cell stem-like properties and the EMT phenotype through the activation of Notch signaling not via autophagy, and using the Notch signaling inhibitor DAPT attenuated the effects of ATG4A on gastric cancer cells. Taken together, these findings demonstrated that ATG4A promotes the metastasis of gastric cancer cells via the Notch signaling pathway, which is an autophagy-independent mechanism.