Glucose-regulated protein 94 mediates progression and metastasis of esophageal squamous cell carcinoma via mitochondrial function and the NF-kB/COX-2/VEGF axis

Abstract

// Chien-Yu Huang 1, 2, * , Chia-Hwa Lee 3 , Chao-Chiang Tu 4, 5, * , Chih-Hsiung Wu 1, 2, 10 , Ming-Te Huang 1, 2 , Po-Li Wei 1, 6, 7, 8, 9 and Yu-Jia Chang 4, 7 1 Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan 2 Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan 3 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 Division of General Surgery, Department of Surgery, Fu Jen Catholic University Hospital; School of Medicine, College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan 6 Division of Colorectal Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 7 Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan 8 Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan 9 Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan 10 En Chu Kong Hospital, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Yu-Jia Chang, email: r5424012@tmu.edu.tw Po-Li Wei, email: poliwei@tmu.edu.tw Keywords: ESCC; GRP94; VEGF; COX-2 Received: July 03, 2017      Accepted: December 01, 2017      Published: January 10, 2018 ABSTRACT Esophageal cancer is a worldwide health problem with a very poor prognosis. Therefore, new diagnostic biomarkers or therapeutic strategies for identifying and managing esophageal squamous cell carcinoma (ESCC) are urgently needed. Glucose-regulated protein 94 (GRP94) is one of major endoplasmic reticulum-stress response proteins that plays a key role in cancer progression and therapeutic responses. However, the role of GRP94 in ESCC progression and metastasis remains unclear. The tissue array results indicated that higher GRP94 expression levels were associated with lower overall survival and higher lympho-node metastasis. Silencing GRP94 (GRP94-KD) reduced cell proliferation, migration and invasion in ESCC cells. In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo. Transmission electron microscopy revealed impaired mitochondria in GRP94-KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells. Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK. In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells.