REG4 promotes peritoneal metastasis of gastric cancer through GPR37

Abstract

// Hexiao Wang 1, * , Lei Hu 1, * , Mingde Zang 1 , Baogui Zhang 2 , Yantao Duan 1 , Zhiyuan Fan 1 , Jianfang Li 1 , Liping Su 1 , Min Yan 1 , Zhenggang Zhu 1 , Bingya Liu 1 , Qiumeng Yang 1 1 Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China 2 Affiliated Hospital of Jining Medical University, Department of Surgery, Jining 272000, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Qiumeng Yang, e-mail: yangqiumeng@hotmail.com Bingya Liu, e-mail: liubingya@sjtu.edu.cn Keywords: gastric cancer, peritoneal metastasis, REG4, adhesion, positive feedback Received: November 5, 2015     Accepted: March 14, 2016     Published: March 28, 2016 ABSTRACT Being the major reason of recurrence and death after surgery, peritoneal metastasis of gastric cancer dooms the prognosis of advanced gastric cancer patients. Regenerating islet-derived family, member 4 (REG4) is believed to promote peritoneal metastasis, however, its mechanism is still a moot point at present. In the present study, we show that high expression of REG4 correlates with advanced stage and poor survival prognosis for gastric cancer patients. REG4 overexpression significantly enhances peritoneal metastasis by increasing adhesion ability. Moreover, SP1 is proved to be a transcription factor of REG4 and induce REG4 expression upon TGF-alpha stimulation. Also, G protein-coupled receptor 37 (GPR37) is identified to be in the same complex of REG4, which mediates REG4’s signal transduction and promotes peritoneal metastasis of gastric cancer cell. Interestingly, we also discover a positive feedback loop triggered by REG4, amplifying itself through EGFR transactivation, consisting of GPR37, ADAM17, TGF-alpha, EGFR, SP1 and REG4. In conclusion, REG4 promotes peritoneal metastasis of gastric cancer through GPR37 and triggers a positive feedback loop.