GRP78-DYRK2相互作用对胃癌转移的影响及分子机制

胃癌转移严重影响患者预后，而越来越多的研究显示内质网应激（endoplasmic reticulum stress，ERS）与肿瘤转移相关，GRP78是内质网应激诱导表达的关键蛋白。本课题组已论证了胃癌组织中GRP78的表达和淋巴结转移相关，并发现其可调节E-cadherin的表达，课题组发现和GRP78直接相互作用的蛋白―双特异性酪氨酸磷酸化调节激酶2（DYRK2），有报道它可以通过调节EMT诱导因子Snail的磷酸化水平促进乳腺癌转移。本课题组拟证明GRP78与DYRK2相互作用，调节Snail磷酸化，导致EMT发生，进而增强胃癌细胞迁移能力的假说。拟在组织水平检测DYRK2、GRP78的表达与临床的联系，然后以胃癌细胞株为模型，探讨其对Snail及下游的调节对胃癌转移的影响，最后在裸鼠体内加以验证。该研究有助于阐明胃癌转移的新的分子机制，为临床治疗提供新的理论依据。

The metastasis of gastric cancer has a serious impact on the prognosis of patients with gastric cancer, and a increasing number of studies have shown that endoplasmic reticulum stress (endoplasmic reticulum stress, ERS) associated with tumor metastasis. GRP78 is a key protein of endoplasmic reticulum stress. Our previous research has found that GRP78 expression was positively correlated with lymph node metastasis in gastric cancer tissues, and could regulate the expression of E-cadherin. In addition, we also found a protein-double specificity of tyrosine phosphorylation regulating kinase 2(DYRK2)which can interact with GRP78 directly. DYRK2 can promote the breast cancer metastasis through regulating the epithelial mesenchymal transition(EMT) inducing factor Snail in the phosphorylation level. We want to demonstrate the hypothesis that the interaction of GRP78-DYRK2 can regulate the phosphorylation of Snail, leading to the occurrence of EMT, thus enhancing the gastric cancer cell migration. In conclusion, firstly we aim to clarify the expression of DYRK2,GRP78 and their association with the gastric clinical specmens. Furthermore, we will explore the effect of Snail and its downstream on the metastasis of gastric cancer in gastric cells, finally we will verify that in nude mice in vivo. The study will help suggest a new molecular mechanism of gastric cancers metastasis,and provide a new theoretical basis for clinical treatment.