REG4 promotes peritoneal metastasis of gastric cancer through GPR37
REG4 promotes peritoneal metastasis of gastric cancer through GPR37
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REG4通过GPR37促进胃癌腹膜转移
DOI：
10.18632/oncotarget.8442
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发表时间：
2016-05-10
期刊：
影响因子：
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通讯作者：
Yang, Qiumeng
中科院分区：
文献类型：
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作者：
Wang, Hexiao;Hu, Lei;Yang, Qiumeng
胃癌腹膜转移是胃癌术后复发和死亡的主要原因，严重影响进展期胃癌患者的预后。再生胰岛衍生家族成员4（Regenerating islet derived family，member 4，REG 4）被认为促进腹膜转移，但其机制目前仍不清楚。在本研究中，我们发现REG 4的高表达与胃癌患者的晚期和不良生存预后相关。REG 4过表达通过增加粘附能力显著增强腹膜转移。此外，SP1被证明是REG 4的转录因子，并在TGF-α刺激下诱导REG 4表达。此外，G蛋白偶联受体37（GPR 37）与REG 4位于同一复合物中，介导REG 4的信号转导，促进胃癌细胞的腹膜转移。有趣的是，我们还发现了一个由REG 4触发的正反馈环，通过EGFR反式激活来放大自身，由GPR 37，ADAM 17，TGF-α，EGFR，SP1和REG 4组成。总之，REG 4通过GPR 37促进胃癌腹膜转移，并触发正反馈回路。
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.