GALNT6介导β-catenin信号在乳腺癌发生发展和转移中的作用及分子机制

Breast cancer, as one of the most common malignant tumor of female, which progression and metastasis meet the challenge of modern medicine, and its internal mechanism is still unclear. Abnormal glycosylation is closely related to tumor progression and metastasis. Our research is focus on glycosyltransferase regulation the tumor development and metastasis. Our previous studies shows that GALNT6 is abnormally expressed in breast cancer, and interference GALNT6 expression can significantly inhibit the tumor behavior of breast cancer cells. In vitro experiments shows that GALNT6 can inhibit breast cancer cell adhesion, promote cell migration and invasion. Further study shows that GALNT6 can regulate the expression and distribution of β-catenin, promote its nuclear transfer, activate the downstream signal factor (Cyclin D1 and C-myc) expression, and indicating that GALNT6 may exert its function through regulation of Wnt/β-catenin signaling pathway. In this project, on the basis of in vitro and in vivo model, we propose to multi-angle validation the mechanism of GALNT6 in the development and metastasis in breast cancer, expose its regulation pathway and potential target molecular, and investigate the interaction model. The results may provide potential biomarkers and therapeutic targets served for the diagnosis andtherapies of breast cancer.

乳腺癌的发展和转移仍是现代医学的难题，其内在的机制尚不够清晰。异常糖基化与肿瘤的进展和转移密切相关，申请人关注于糖基转移酶对肿瘤进展和转移的调控，在前期研究中我们发现GALNT6在乳腺癌中异常表达，干扰GALNT6的表达能显著抑制乳腺癌细胞的肿瘤行为。在体外实验中GALNT6能抑制乳腺癌细胞间的粘附作用，促进细胞的迁移和侵袭；进一步研究表明，GALNT6不仅能调节β-catenin的表达而且能改变其分布，促进其转核，激活下游信号因子（Cyclin D1和C-myc）的表达；提示GALNT6可能通过调节Wnt/β-catenin信号通路发挥其功能。本项目拟在此基础上结合体外实验和体内动物模型，多角度验证GALNT6在乳腺癌发生发展和转移中的分子机制，解析其发挥功能效应的途径及作用标靶，鉴定分子相互作用的精细模式，为乳腺癌的诊断和治疗提供潜在的生物标志物和治疗靶标奠定基础。

乳腺癌是女性最常见的恶性肿瘤之一，乳腺癌的复发和转移仍是现代医学的难题，其内在的机制尚不够清晰。异常糖基化与肿瘤的进展和转移密切相关，而异常糖基化修饰的本质是糖基转移酶功能或结构的异常。本项目以乳腺癌为研究对象，通过构建GALNT6低表达（高表达））乳腺癌细胞株，全面探讨了GALNT6对乳腺癌细胞生物学功能的影响。结果表明GALNT6能促进乳腺癌细胞的增殖、迁移侵袭，抑制乳腺癌细胞的凋亡和分化。GALNT6能通过抑制E-cadherin的表达，减少β-catenin在细胞膜上的分布，抑制GSK3β的活化，降低β-catenin的磷酸化，阻止β-catenin在胞浆中的降解；另一方面GALNT6通过对MUC1糖基化，产生的MUC1-C与β-catenin结合，协助β-catenin的入核，进而促进相关促癌基因的表达；进而导致乳腺癌的发生及其恶化。在此基础上，研究发现GALNT6可能通过调控TRII的表达及其糖基化水平诱导TGF-β信号通路的激活，进而促进乳腺癌细胞的EMT进程。研究结果为全面了解GALNT6促进乳腺癌发生发展的作用机制提供了实验基础和理论依据，为乳腺癌的诊断和治疗提供潜在的生物标志物和治疗靶标奠定基础。