Research Papers:

REG4 promotes peritoneal metastasis of gastric cancer through GPR37

Hexiao Wang _, Lei Hu, Mingde Zang, Baogui Zhang, Yantao Duan, Zhiyuan Fan, Jianfang Li, Liping Su, Min Yan, Zhenggang Zhu, Bingya Liu and Qiumeng Yang

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Oncotarget. 2016; 7:27874-27888. https://doi.org/10.18632/oncotarget.8442

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Hexiao Wang1,*, Lei Hu1,*, Mingde Zang1, Baogui Zhang2, Yantao Duan1, Zhiyuan Fan1, Jianfang Li1, Liping Su1, Min Yan1, Zhenggang Zhu1, Bingya Liu1, Qiumeng Yang1

1Shanghai 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

2Affiliated 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: [email protected]

Bingya Liu, e-mail: [email protected]

Keywords: gastric cancer, peritoneal metastasis, REG4, adhesion, positive feedback

Received: November 5, 2015    Accepted: March 14, 2016    Published: March 28, 2016


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.

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