MIF糖基化缺失导致EGFR激活促进Lewis抗原阴性胰腺癌侵袭转移的实验研究

Pancreatic cancer is a highly lethal malignancy and patients with pancreatic cancer have prognosis. CA19-9 is the most important biomarker for pancreatic cancer and its secretion closely correlates to tumor burden and stage. Lewis antigen, also called fucosyltransferase 3 or FUT3, can modulate protein function by glycosylation modification. It is also the key enzyme of glycosylation modification during CA19-9 synthesis. Lewis antigen negative patients with pancreatic cancer, constituting 6.8% of all patients, have no CA19-9 secretion for the absence of FUT3.We previously found that Lewis antigen negative pancreatic cancer is a special subgroup with highly invasive potential and without FUT3 glycosylation. MIF (macrophage migration inhibitory factor) plays an important role in the invasion and metastasis of Lewis negative pancreatic cancer and MIF without glycosylation can activate EGFR related signal pathway. Moreover, EGFR (epidermal growth factor receptor) is overexpressed and excessive activated in this subgroup. Therefore, we hypothesized that MIF without FUT3 related glycosylation can promote the progression of Lewis negative pancreatic cancer by activating EGFR related signal pathway. This study will explore the molecular mechanism of Lewis negative pancreatic cancer based on the previous established subgroup. It will provide theoretical basis for using FUT3-MIF-EGFR pathway as a therapeutic target in Lewis negative pancreatic cancer.

胰腺癌恶性程度高，预后差。CA19-9是胰腺癌最重要的标志物，其水平与胰腺癌分期密切相关。Lewis抗原又名岩藻糖基转移酶3或FUT3，是CA19-9糖基化修饰的关键酶。6.8%的患者为Lewis抗原阴性个体，该亚群糖基转移酶缺失而无法正常合成CA19-9。前期研究表明，Lewis抗原阴性胰腺癌具有高度侵袭转移特性，是FUT3糖基化缺失的特殊亚群，MIF (巨噬细胞移动抑制因子) 在Lewis抗原阴性胰腺癌中糖基化缺失，而MIF糖基化缺失可激活EGFR信号通路。因此我们推测：FUT3失活引起MIF糖基化缺失导致EGFR信号通路过度激活从而促进Lewis抗原阴性胰腺癌侵袭转移。本研究以前期甄别的Lewis抗原阴性胰腺癌亚群为基础，以FUT3-MIF-EGFR功能轴为研究靶点，探索Lewis抗原阴性胰腺癌高度侵袭转移的潜在分子机制，从而为胰腺癌的治疗提供理论依据。

胰腺癌恶性程度高，预后差。CA19-9是胰腺癌最重要的标志物，其水平与胰腺癌分期密切相关。Lewis抗原又名岩藻糖基转移酶3或FUT3，是CA19-9糖基化修饰的关键酶。6.8%的患者为Lewis抗原阴性个体，该亚群糖基转移酶缺失而无法正常合成CA19-9。前期研究表明，Lewis抗原阴性胰腺癌具有高度侵袭转移特性，是FUT3糖基化缺失的特殊亚群，MIF (巨噬细胞移动抑制因子) 在Lewis抗原阴性胰腺癌中糖基化缺失，而MIF糖基化缺失可激活EGFR信号通路。本项目进一步研究发现，EGFR在Lewis 抗原阴性胰腺癌中表达增高，是Lewis抗原阴性胰腺癌的关键效应分子。Lewis阴性胰腺癌中存在FUT3功能缺失，导致MIF的糖基化受抑制。MIF糖基化缺失诱导MIF过度激活，进一步使得EGFR活性增加，且MIF与EGFR存在相互作用，引起肿瘤进展。因此，EGFR通过FUT3-EGFR-MIF功能轴发挥促癌作用，促进了Lewis阴性胰腺癌的侵袭转移，EGFR以及MIF是Lewis阴性胰腺癌的潜在治疗靶点。