Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
Sci Rep. 2016 Jun 13;6:27853. doi: 10.1038/srep27853.
O-GlcNAcylation, an O-linked protein glycosylation with a single molecule of N-acetylglucosamine (GlcNAc), is reversibly controlled by O-GlcNAc transferase (OGT) and N-acetyl D-glucosaminidase (OGA). Aberrant O-GlcNAcylation contributes an important role in initiation and progression of many human cancers. Elevation of O-GlcNAcylation in tumor tissues and poor prognosis of cholangiocarcinoma (CCA) patients have been reported. In this study, the role of O-GlcNAcylation in promoting tumor progression was further investigated in CCA cell lines. Suppression of O-GlcNAcylation using small interfering RNAs of OGT (siOGT) significantly reduced cell migration and invasion of CCA cells whereas siOGA treated cells exhibited opposite effects. Manipulating levels of O-GlcNAcylation did affect the nuclear translocation of NF-κB and Akt-phosphorylation together with expression of matrix-metalloproteinases (MMPs). O-GlcNAcylation and nuclear translocation of NF-κB, the upstream signaling cascade of MMP activation were shown to be important for MMP activation. Immunoprecipitation revealed the elevation of O-GlcNAc-modified NF-κB with increased cellular O-GlcNAcylation. Involvement of O-GlcNAcylation in MMP-mediated migration and invasion of CCA cells was shown to be via O-GlcNAcylation and nuclear translocation of NF-κB. This information indicates the significance of O-GlcNAcylation in controlling the metastatic ability of CCA cells, hence, O-GlcNAcylation and its products may be new targets for treatment of metastatic CCA.
O-糖基化，一种带有单个 N-乙酰葡萄糖胺（GlcNAc）的 O-连接蛋白糖基化，可被 O-连接糖基转移酶（OGT）和 N-乙酰-D-葡萄糖胺酶（OGA）可逆调控。异常的 O-糖基化在许多人类癌症的发生和发展中起着重要作用。已经报道了肿瘤组织中 O-GlcNAcylation 的升高和胆管癌（CCA）患者预后不良。在这项研究中，进一步研究了 O-GlcNAcylation 在促进 CCA 细胞系肿瘤进展中的作用。使用 OGT（siOGT）的小干扰 RNA 抑制 O-GlcNAcylation 显著降低了 CCA 细胞的迁移和侵袭，而 siOGA 处理的细胞则表现出相反的效果。操纵 O-GlcNAcylation 的水平确实会影响 NF-κB 的核转位和 Akt 磷酸化以及基质金属蛋白酶（MMPs）的表达。O-GlcNAcylation 和 NF-κB 的核转位，MMP 激活的上游信号级联，被证明对 MMP 激活很重要。免疫沉淀显示随着细胞 O-GlcNAcylation 的增加，O-GlcNAc 修饰的 NF-κB 水平升高。O-GlcNAcylation 参与 MMP 介导的 CCA 细胞迁移和侵袭是通过 O-GlcNAcylation 和 NF-κB 的核转位。这些信息表明 O-GlcNAcylation 在控制 CCA 细胞的转移能力方面具有重要意义，因此，O-GlcNAcylation 及其产物可能成为转移性 CCA 治疗的新靶点。
