GALNT6介导Daple蛋白FZD结合域O-糖基化调控乳腺癌侵袭转移的分子机制研究

蛋白异常糖基化异常在实体瘤中普遍存在，课题组前期研究发现O-糖基化关键调节酶GALNT6参与乳腺癌发生发展。非经典Wnt激活因子Daple被报道在乳腺癌患者血清中高表达，与EMT转化密切相关。申请人应用串联质谱分析法预测GALNT6的O-糖基化的底物，发现Daple蛋白的FZD结合区里6个丝/苏氨酸被糖基化，这些区域的糖基化可能稳定Daple蛋白。结合文献报道及相关研究成果我们推测：GALNT6参与乳腺癌发生，通过O-糖基化修饰调控Daple蛋白稳定，激活Wnt非经典信号通路，促进乳腺癌EMT转化和侵袭转移。为此本项目将多水平探讨GALNT6糖基化Daple的FZD结合区域调控乳腺癌进展的具体分子机制，根据Daple糖基化位点设计合成细胞穿膜肽，验证Daple蛋白糖基化后在乳腺癌细胞侵袭转移中的作用，为乳腺癌的同步治疗提供新的视野和方向。

Abnormal glycosylation of protein is common in solid tumors. Our previous study found that GALNT6, a key regulator of O-glycosylation, was involved in the development of breast cancer. Non-canonical Wnt signaling activator Daple has been reported to be highly expressed in the serum of breast cancer patients and is closely related to epithelial-mesenchymal transition (EMT). The applicant used tandem mass spectrometry to predict the o-glycosylated substrates of GALNT6 and found that six serine/threonine in the FZD-binding regions of Daple protein were glycosylated and which might stabilize the Daple protein. Therefore, combining with literature reports and related research results, we speculated that GALNT6 is involved in the development of breast cancer, regulating Daple protein stability through O-glycation modification, activating non-canonical Wnt signaling, fuelling EMT and trigger cancer cell migration and invasion. We will elucidate the mechanism onmulti-level of GALNT6 glycosylation FZD of Daple regulating breast cancer progress, According to the Daple glycosylation sites design and synthesize peptide, to verify the role of Daple protein glycosylation in the invasion and metastasis of breast cancer cells. This topic will provide a new field of vision and direction for the synchronous treatment of breast cancer.