GRP78-DYRK2相互作用对胃癌转移的影响及分子机制

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.

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。

对于胃癌，目前国际公认的治疗原则是以化疗为主的综合治疗，探索新的药物靶点并进行个体化治疗，是近年来胃癌治疗研究重点。因此，探索新的治疗靶点对胃癌的治疗至关重要。本研究一方面研究DYRK2（双重特异性酪氨酸磷酸化调节激酶2）在胃癌发生、发展和耐药中发挥的作用，结果显示DYRK2在胃癌组织与正常胃组织中表达差异显著，在正常胃组织中表达高于胃癌组织，且DYRK2表达高预后好，高表达DYRK2抑制胃癌的增殖、迁移和侵袭能力，同时发现增强DYRK2的表达可以缓解在胃癌治疗中L-OPH的耐药性，另一方面研究DYRK2对胃癌细胞的自噬水平的调节情况，研究结果显示DYRK2促进自噬的产生。研究过程中，我们还发现RhCG，TREM2，EPHA8，PHGDH，KIF2A，FIBCD1，NDUFS1，NDUFS2，NDUFS3，NDUFS4，NDUFS5，NDUFS6，NDUFS7，NDUFS8在胃癌组织中表达有差异，且RhCG，TREM2，EPHA8，PHGDH，KIF2A，FIBCD1，NDUFS2，NDUFS4，NDUFS8为表达高预后差，NDUFS1，NDUFS3，NDUFS5，NDUFS6，NDUFS7表达高预后好，其中RhCG通过保持细胞内碱性促进胃癌的迁移和增殖，EPHA8通过调节ADAM10导致胃癌预后不良。研究拟为临床开展DYRK2，RhCG，TREM2，EPHA8，PHGDH，KIF2A，EPHA8，FIBCD1表达差异的胃癌治疗提供参考依据，为后续相应的临床研究提供基础。