ADAMTS5抑制Ets-1介导的血管生成调控胃癌侵袭转移的机制研究

我们发现ADAMTS5与胃癌侵袭转移相关，但机制不详。前期研究提示ADAMTS5可能通过PI3K/AKT通路抑制Ets-1诱导的血管生成调节胃癌侵袭转移。基于此假说，IHC和qRT-PCR检测ADAMTS5、Ets-1和CD31在胃癌中的表达及相关性；构建ADAMTS5、Ets-1高/低表达细胞，分子生物技术检测胃癌细胞侵袭能力、PI3K/AKT和Ets-1的表达及血管生成；RNA干扰、通路激活剂等方法研究ADAMTS5抑制Ets-1介导的血管生成调节胃癌侵袭转移；荧光素酶报告基因等法探讨ADAMTS5通过PI3K/AKT通路调控Ets-1的详细机制。动物模型验证ADAMTS5下调Ets-1减少MVD抑制胃癌侵袭转移。体内外实验阐明ADAMTS5调节PI3K/AKT/Ets-1通路减少血管生成抑制胃癌侵袭转移的分子机制。本研究对补充胃癌侵袭转移的分子机制，探寻新的转移标志物有一定的意义。

ADAMTS5 is involved in the invasion and metastasis of gastric cancer, however, the underlying mechanism remains unknown. Our previous studies suggest that ADAMTS5 may inhibit invasion and metastasis by suppression of the Ets-1-induced angiogenesis via inactivating PI3K/AKT pathway of gastric cancer. Based on this hypothesis, IHC and qRT-PCR were used to detect the expression and analyze the correlation of ADAMTS5, Ets-1 and CD31 in gastric cancer tissues and gastric cancer cells. Stable cells with over-expression/knock-down of ADAMTS5 or Ets-1 were established and subsequently used to explore the effects of ADAMTS5 on invasive ability of gastric cancer cells, PI3K/AKT and Ets-1 expression and angiogenesis by biological methods. Methods of RNA interference, pathway activator were employed to assess the roles of PI3K/AKT pathway and Ets-1 on the inhibition of angiogenesis and invasion and metastasis by ADAMTS5 of gastric cancer; Methods of luciferase reporter gene and immunoprecipitation were adopted to evaluate the mechanism of ADAMTS5 regulate PI3K/AKT pathway and Ets-1. Finally, animal models were conducted to verify that ADAMTS5 down-regulates Ets-1 to reduce MVD and inhibits invasion and metastasis of gastric cancer. In vitro and in vivo experiments demonstrated the molecular mechanism of ADAMTS5 inhibits PI3K/AKT/Ets-1 pathway to reduce angiogenesis and suppress the invasion and metastasis of gastric cancer. The clinical implication of this study is to provide some evidence to elucidate the molecular mechanism of invasion and metastasis of gastric cancer, and to seek a potentially novel target predicting metastasis in gastric cancer.