MUC16 C-terminal/AKT/HK2信号轴在Lewis抗原阴性胰腺癌侵袭转移中的作用及机制研究

我们前期发现临床上存在特殊胰腺癌人群（5-10%），其岩藻糖基化转移酶FUT3无功能、血清标志物CA19-9不表达、易早期转移、预后差，称为Lewis阴性胰腺癌。进一步研究发现该人群具有特殊分子特征：1. 粘蛋白MUC16高表达; 2. 岩藻糖基化缺失。而岩藻糖基化缺失导致的关键糖蛋白构象功能改变，可促使MUC16功能肽段MUC16C-terminal释入胞浆，并通过活化AKT信号通路，上调糖酵解关键酶HK2表达，发挥促癌作用。基于上述基础，本研究拟阐明Lewis阴性胰腺癌中岩藻糖基化缺失对关键糖蛋白、糖基化位点的影响，进一步探究MUC16C-terminal释入胞浆的具体机制，评价MUC16C-terminal/AKT/HK2信号轴的运转对胰腺癌细胞通过无氧代谢（Warburg效应）获能生存、获得高侵袭转移特性的影响，并通过临床标本检测，获得Lewis阴性胰腺癌人群特异的诊断、预后标志。

Our previous work found that Lewis antigen-negative pancreatic cancer, characterized by non-functional fucosyltransferase FUT3 and non-expression of serum marker CA19-9, is viewed clinically as a peculiar subgroup (about 5-10%)of more aggressive pancreatic cancer and susceptible to developing early metastasis associated with a poor prognosis. Elevated MUC16(Mucin 16) expression and fucosylation deficiency have recently been publicly acknowledged as two distinctive molecular features of this subgroup population. The conformational and functional changes of certain glycoproteins caused by fucosylation deficiency, facilitating release of the functional peptide of MUC16, MUC16 C-terminal, into the cytoplasm, and then, upregulating the expression of HK2, a pivotal enzyme of glycolysis, and eventually triggering carcinogenesis via activating AKT signal pathway. On the ground of above work, this research intends to illustrate the effect of fucosylation deficiency on the key glycoproteins/glycosylated peptides and glycosylation sites in Lewis antigen-negative pancreatic cancer, and further exploring the concrete mechanism of MUC16 C-terminal release into the cytoplasm. Our proposal highlights the MUC16 C-terminal/AKT/HK2 axis mediated modulation of pancreatic cancer cell-autonomous survival, unparalleled invasiveness, and metastasis by means of anaerobic metabolism (the Warburg Effect). Concurrently, specific diagnostic and prognostic signatures of Lewis antigen-negative subgroup are identified with a comprehensive analysis of tissue and serum in pancreatic cancer patients.