TNIP2突变体（TNIP2-T111I）与TEK相互作用在胆囊癌淋巴转移中的作用及调控机制研究

淋巴转移是胆囊癌最常见的转移方式，也是影响其治疗和预后的重要因素。我们前期利用全基因组外显子测序等技术发现TNIP2在胆囊癌淋巴转移病人中发生高频突变，其中T111I是突变的热点区域；功能实验发现TNIP2-T111I可促进胆囊癌的增殖及淋巴转移能力，提示TNIP2-T111I在胆囊癌淋巴转移中发挥重要作用。进一步通过免疫共沉淀等方法，筛选出TNIP2-T111I的相互作用蛋白TEK。据此我们提出假说，TNIP2-T111I通过与TEK蛋白相互作用后促进了胆囊癌淋巴转移。本课题拟从分子、细胞、组织以及动物水平等多层次探究TNIP2-T111I与TEK蛋白的相互作用及在胆囊癌淋巴转移过程中的分子调控机制，从而加深对胆囊癌淋巴转移相关分子调控网络的理解，明确TNIP2-T111I作为胆囊癌干预新靶点的临床意义，为胆囊癌的临床诊断标志物和靶向药物开发提供理论依据。

Lymphatic metastasis, as the most common type of gallbladder cancer (GBC) metastasis, is a crucial factor that determines the treatment and prognosis of GBC. In our previous study, we found that TNIP2 mutated frequently in GBC patients with lymphatic metastasis by using whole exome sequencing technology. In addition, T111I mutation of TNIP2 was discovered as the “hot-spot” mutation. Subsequent functional experiments indicated that TNIP2-T111I could promote the proliferation and lymphatic metastasis of GBC, suggesting that TNIP2-T111I played an important role in the lymphatic metastasis of GBC. Co-immunoprecipitation experiments revealed TEK as an interacting protein of TNIP2-T111I in GBC. Based on these results, we hypothesized that TNIP2-T111I promoted lymphatic metastasis of GBC by interacting with TEK protein. In the present project, we aim to validate the interaction between TNIP2-T111I and TEK protein and unveil the related molecular regulation mechanism in lymphatic metastasis of GBC at molecular, cellular, tissue and animal levels. Our study will deepen the understanding of the molecular regulatory network related to lymphatic metastasis of GBC and clarify TNIP2-T111I as a potential target of GBC treatment. These findings will provide theoretical basis for the development of diagnostic markers and targeted therapies of GBC.