岩藻糖基化修饰经TLR4/Myd88信号通路介导卵巢癌紫杉醇耐药的实验研究

Lewis y is a difucosylated oligosaccharide on the cell surface，which is a tumor associated carbohydrate antigen and has a wide range of application prospects in early screening and biological treatment of tumor. Previously, we transfected the gene of key enzyme responsible for the synthesis of Lewis y into human ovarian cancer cells, and established the stable Lewis y antigen high expression cell line. We found that, compared with those before transfection, tansfected cells showed significantly increased resistance to paclitaxel. However, the mechanism is unclear. Paclitaxel is a natural ligand of TLR4 on cell surface, when paclitaxel stimulates TLR4/MyD88 pathway and activates the Akt and NF-κB pathway, tumor cells are caused apoptosis resistance and induced to release immunosuppressive cytokines, and eventually lead to the failure of chemotherapy. TLR4 is a transmembrane glycoprotein, we therefore speculate that Lewis y antigen regulates TLR4/MyD88 pathway as a part of TLR4 structure. The purpose of this project is to reveal the mechanism and the role of fucosylation in promoting the occurrence of paclitaxel resistance in ovarian cancer by proving that Lewis y induces paclitaxel resistance in ovarian cancer through TLR4/Myd88 and its downstream pathways, thus to provide theory evidence for inhibition of tumor recurrence and metastasis and drug resistance inverse by targeting Sugar chain.

Lewis y是细胞膜表面双岩藻糖基化的寡糖，是肿瘤相关糖抗原，在肿瘤早期筛查、生物学治疗等方面有广泛的应用前景。前期我们将Lewis y合成关键酶基因转染入人卵巢癌细胞，建立了Lewis y稳定高表达细胞模型。研究发现，与转染前相比，卵巢癌细胞对紫杉醇的耐药性明显增强，但其机制并不清楚。紫杉醇是细胞表面受体TLR4的固有配体，当紫杉醇刺激TLR4/MyD88通路时激活Akt和NF-κB通路，引起肿瘤细胞凋亡抵抗、诱导肿瘤细胞释放免疫抑制因子，最终导致化疗失败。TLR4为跨膜糖蛋白，我们推测Lewis y作为TLR4结构的一部分参与TLR4/MyD88通路调节。本课题利用紫杉醇与TLR4的固有关系，通过证明Lewis y经TLR4/Myd88及其下游通路介导卵巢癌紫杉醇耐药，揭示岩藻糖基化修饰在促进卵巢癌紫杉醇耐药发生中的机制和作用，为以糖链为靶点抑制肿瘤复发转移及逆转耐药提供理论依据。