Noggin通过β-catenin/EGFR/Akt通路促进胃癌增殖的分子机制研究

Noggin是骨形态发生蛋白的胞外拮抗剂，在胃癌中作用机制不明。本课题组前期研究表明Noggin高表达胃癌患者生存期仅为低表达者的1/3。体外实验证实Noggin可促进胃癌细胞增殖，并伴有EGFR信号通路异常激活。进一步研究发现Noggin活化EGFR通路是由β-catenin介导：Noggin促进β-catenin转移至细胞核，增加EGFR基因的转录和蛋白表达；反之EGFR-AKT通路活化进一步促进β-catenin的核转运，形成环路活化，促进胃癌细胞增殖。β-catenin抑制剂可阻断Noggin介导的EGFR表达，从而抑制胃癌细胞增殖。但Noggin调控 β-catenin的分子机制尚无报道。本项目拟通过基因表达谱芯片、荧光素酶报告基因、CHIP等方法检测Noggin调控β-catenin通路的分子机制，并在动物模型及组织标本中加以验证，为胃癌治疗寻找新的靶点。

Noggin is an extracellular antagonist of bone morphogenetic protein, and the knowledge about involvement of Noggin in gastric cancer remains poor. Our previous study suggested that the overall survival of GC patients with high expression of Noggin was only 1/3 of those with low expression. In vitro studies showed that Noggin could significantly promote gastric cancer cell proliferation with abnormal activation of EGFR signaling pathway. Further studies revealed that Noggin-activated EGFR pathway was mediated by β-catenin: Noggin promoted the transfer of β-catenin to the nucleus and increased the transcription and protein expression of EGFR gene; whereas the activation of EGFR-AKT pathway further promoted nuclear translocation of β-catenin, formed a loop and promoted the proliferation of gastric cancer cells. β-catenin inhibitors could block Noggin-mediated EGFR expression, thereby inhibited the proliferation of gastric cancer cell. However, the molecular mechanism by which Noggin regulates β-catenin has not been reported. It is proposed to explore the molecular mechanism of the activation of β-catenin pathway by Noggin through gene expression array, luciferase reporter gene assay, CHIP and validate the results in animal models and tissue specimens. It is expected that these results will provide new ideas for new therapeutic targets of gastric cancer.