AEG-1磷酸化修饰在胃癌转移中作用机制的研究

胃癌在我国癌症相关死亡中居第二位，肿瘤转移是患者死亡的重要原因。星型胶质细胞上调基因1（AEG-1）在胃癌转移中发挥重要作用，但其分子机制仍不明确。磷酸化和去磷酸化修饰是蛋白功能调控的重要方式，目前关于AEG-1磷酸化修饰的调控鲜有报道。我们前期研究发现AEG-1的426位丝氨酸去磷酸化增强了AEG-1的活性，上调了肿瘤转移促进因子eIF4E的表达；蛋白质谱的研究发现一个具有磷酸酶调节亚单位特征的新蛋白PPP1R21，与AEG-1存在直接结合。由此，我们提出假设：PPP1R21介导的AEG-1去磷酸化，促进了eIF4E的转录表达，进而促进胃癌转移。我们将从分子、细胞、整体动物水平以及人组织样品中的检测，明确AEG-1去磷酸化修饰在胃癌转移中的重要作用，阐明AEG-1去磷酸化修饰的分子调控机制，从而为防治胃癌转移提供新的诊断指标、治疗靶点和策略。

Gastric cancer is the second leading cause of cancer related death in China. Metastasis is the main cause of mortality. Astrocyte elevated gene-1 (AEG-1), as an oncogene, is proved to play an important role in the metastasis of gastric cancer; however, its mechanism hasn’t been fully clarified. Phosphorylation and dephosphorylation modification play a pivotal role in regulation of protein function. Currently, the phosphorylation modification of AEG-1 has seldom investigated. We found that the dephosphorylation of AEG-1 at Serine 426 activated AEG-1 and upregulated the expression of pro-metastatic eIF4E. Proteomics analysis showed that protein phosphatase 1 regulatory subunit 21 (PPP1R21) interacted with AEG-1. Therefore, we hypothesized that PPP1R21-mediated AEG-1 dephosphorylation promotes gastric cancer metastasis through upregulation of eIF4E expression. In this study, we will evaluate the role of AEG-1 dephosphorylation in the metastasis of gastric cancer and clarify the mechanism of AEG-1 dephosphorylation in cell lines, animal models, and human tissue samples. Our findings will suggest new diagnostic markers, therapeutic targets, and strategies for gastric cancer therapy.