EphA2调控胃癌Wnt/β-catenin通路的分子机制及其临床意义

EphA2 belongs to the family of receptor tyrosine kinases, functioning in bi-directional transduction via a mutual contaction with adjacent cells expressing its specific ligand EphrinA1. This behavior promotes tumor invasion and metastasis and is one of the hotspots on the oncological researches. Recently,our research team firstly reported that EphA2 could promote epithelial-mesenchymal transition (EMT) in gastric cancer cells through activation of Wnt/β-catenin signaling. And we also newly found that EphA2 can effect the mRNA levels of multiple regulating proteins in Wnt/β-catenin pathway and immunofluorescent staining revealed co-localization of EphA2 and Wnt1 on membranes in gastric cancer cells. On the basis of these findings, we hypothesize that: EphA2 regulates Wnt/β-catenin pathway via transcriptional mechanisms and receptor-ligand pattern in gastric cancer cells. We will use experimental methods and apparatus, including mutants construction, fused proteins preparation, RNA interference, western blot, quantitative PCR, in the molecular, cellular and entire animal levels to probe mechanisms and functional significance in activation of EphA2 bi-directional signaling in gastric cancer cell, as well as how EphA2 regulates Wnt/β-catenin signaling, which is the research focus of this project. To carry out this project is expected to reveal novel mechanism of EphA2 in gastric cancer, to open up new areas for research of tumor invasion and metastasis, to provide fresh train of thought and experimental clues for gastric cancer targeted therapy.

EphA2是受体酪氨酸激酶家族成员，通过与表达其配体EphrinA1的临近细胞接触发挥双向信号转导功能，参与肿瘤侵袭转移，是肿瘤研究的热点之一。项目组最近首次报道异常高表达的EphA2能够活化Wnt/β-catenin通路，诱导胃癌细胞发生上皮-间质转化，新近发现EphA2影响该通路多种调节蛋白的mRNA水平，且与WNT1配体存在膜上共定位关系。申请者在此基础之上提出科学假说 “EphA2通过转录水平及受体-配体模式调控胃癌Wnt/β-catenin通路” ，拟采用突变体构建、融合蛋白制备、RNA干扰、免疫印迹、定量PCR等研究手段，在分子、细胞和整体动物水平，探讨胃癌细胞中EphA2双向信号通路活化的功能意义，其中EphA2如何调控Wnt/β-catenin通路是研究重点。开展本项目可望揭示EphA2在肿瘤中的作用新机制，为肿瘤侵袭转移的研究开辟新的领域，为胃癌的靶向治疗提供新的思路。

EphA2是受体酪氨酸激酶家族成员，通过与表达其配体EphrinA1的临近细胞接触发挥双向信号转导功能，参与肿瘤侵袭转移，是肿瘤研究的热点之一。项目组最近首次报道异常高表达的EphA2能够活化Wnt/β-catenin通路，诱导胃癌细胞发生上皮-间质转化，新近发现EphA2影响该通路多种调节蛋白的mRNA水平，且与WNT1配体存在膜上共定位关系。我们在此基础之上提出科学假说 “EphA2通过转录水平及受体-配体模式调控胃癌Wnt/β-catenin通路” ，拟采用突变体构建、融合蛋白制备、RNA干扰、免疫印迹、定量PCR等研究手段，在分子、细胞和整体动物水平，探讨胃癌细胞中EphA2双向信号通路活化的功能意义，其中EphA2如何调控Wnt/β-catenin通路是研究重点。开展本项目可望揭示EphA2在肿瘤中的作用新机制，为肿瘤侵袭转移的研究开辟新的领域，为胃癌的靶向治疗提供新的思路。