REG4 promotes peritoneal metastasis of gastric cancer through GPR37

• Published in: Oncotarget Vol. 7; no. 19; pp. 27874 - 27888
• Main Authors: Wang, Hexiao, Hu, Lei, Zang, Mingde, Zhang, Baogui, Duan, Yantao, Fan, Zhiyuan, Li, Jianfang, Su, Liping, Yan, Min, Zhu, Zhenggang, Liu, Bingya, Yang, Qiumeng
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 10.05.2016
• Subjects: ADAM17 Protein - metabolism; Aged; Cell Line, Tumor; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Gene Expression Regulation, Neoplastic - genetics; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - mortality; Neoplasm Staging; Pancreatitis-Associated Proteins - genetics; Pancreatitis-Associated Proteins - metabolism; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - mortality; Peritoneal Neoplasms - secondary; Peritoneum - pathology; Prognosis; Receptors, G-Protein-Coupled - metabolism; Research Paper; Signal Transduction; Sp1 Transcription Factor - metabolism; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Transcriptional Activation; Transforming Growth Factor alpha - metabolism; positive feedback; adhesion; gastric cancer; REG4; peritoneal metastasis
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8442

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.