GALNT6调控EPHB6受体O-糖基化修饰促进结直肠癌侵袭转移的作用和机制研究

O-糖基化修饰广泛分布于结直肠粘膜组织，是消化道稳态重要组成部分。糖基转移酶异常表达导致细胞O-糖基化紊乱是结直肠癌恶性转化的重要特征，而O-修饰酶的肿瘤生物学功能、关键修饰靶点及作用有待深入研究。我们前期鉴定了GALNT6在结直肠癌组织中高表达；通过VVA验证GALNT6上调细胞O-GalNAc修饰水平；体内外功能研究发现GALNT6促进结直肠癌细胞迁移侵袭及生长；此外GALNT6与抑癌基因EPHB6直接结合并影响其稳定性。我们推测GALNT6调控EPHB6糖基化修饰促进结直肠癌恶性发展，拟进一步开展以下研究：在细胞和动物模型中进一步验证GALNT6促迁移侵袭的功能；研究EPHB6的T564糖基化修饰对蛋白结构、功能及稳定性的影响；进一步明确GALNT6导致的EPHB6异常修饰的体内外功能表现；并探讨GALNT6相关糖基化修饰在结直肠癌中的临床价值，拟为结直肠癌的诊治提供新的靶标和思路。

O-GalNAc glycosylation modifications are widely distributed in colorectal mucosal tissues and are an important component of the gastrointestinal barrier. Aberrant expression of glycosyltransferases leading to disrupted cellular O-GalNAc glycosylation is an important modification feature of malignant transformation in colorectal cancer, and the tumour biological functions of O-GalNAc-modifying enzymes, key modification targets and their roles in clinical testing need to be investigated in depth. We identified that GALNT6 was highly expressed in colorectal cancer tissues and positively correlated with distal tumour metastasis; we verified that GALNT6 up-regulated cellular O-GalNAc glycosylation modification level by VVA lectin; we found that GALNT6 promoted colorectal cancer cell migration and invasion and growth in ex vivo functional study; we found that GALNT6 directly interacted with oncogene EPHB6 and influenced oncogene in downstream key target mining. In the downstream key target mining, we found that GALNT6 interacts directly with EPHB6 and affects its protein stability. We hypothesize that GALNT6 regulates EPHB6 glycosylation modifications to promote malignant development of colorectal cancer and propose to further investigate the following: to further validate the function of GALNT6 in promoting malignant development of colorectal cancer in cellular phenotypes and animal models; to investigate the effect of T564 site glycosylation modifications of EPHB6 on protein structure, function and stability; to further clarify the effects of GALNT6-induced functional expression of EPHB6 aberrant O-GalNAc glycosylation in vitro and in vivo; and to explore the clinical value of GALNT6-related glycosylation modifications in colorectal cancer. This project intends to provide new targets or ideas for the diagnosis and treatment of colorectal cancer.