Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Laboratory of Cellular and Molecular Biology (LIM 15), Department of Neurology, Faculdade de Medicina, University of São Paulo, São Paulo, SP, Brazil.
Adv Exp Med Biol. 2022;1382:39-70. doi: 10.1007/978-3-031-05460-0_4.
Aberrant glycosylation has been associated with several processes of tumorigenesis from cell signaling, migration and invasion, to immune regulation and metastasis formation. The biosynthesis of glycoconjugates is regulated through concerted and finely tuned enzymatic reactions. This includes the levels and activity of glycosyltransferases and glycosidases, nucleotide sugar metabolism, substrate availability, epigenetic condition, and cellular functional state. Glioblastoma (GBM) is the most aggressive brain tumor, frequently occurring in adults with overall survival not surpassing 17 months after diagnosis. GBM has been classified by the World Health Organization (WHO) as a grade 4 astrocytoma and stratified into G-CIMP, proneural, classical, and mesenchymal subtypes. Several biomolecular features associated with GBM aggressiveness have been elucidated; however, more studies are needed to elucidate the role of glycosylation in GBM pathology, looking at their potential as cancer targets. Here, we focus on the alteration of genes involved in protein N- and O-linked glycosylation in GBM. Specifically, the mRNA levels of glycogenes were analyzed using astrocytoma-TCGA-RNAseq datasets from public repositories. A total of 68 genes were differentially regulated in the most aggressive, mesenchymal subtype of GBM compared to the proneural and classical subtypes, and the expression of these genes was compared to normal brain tissues. Among them, we focused on 38 genes coding for proteins that belong to: 1) asparagine glycosylation (ALG); 2) glycosyltransferases (B3T, B4T); 3) fucosyltransferase (FUT); 4) acetylgalactosaminyltransferases (GALNT); 5) hexosaminidase (HEX); 6) mannosidase (MAN); 7) acetylglucosaminyltransferase (MGAT); 8) sialidase or neuraminidase (NEU); 9) solute carrier 35 family (SLC); and 10) sialyltransferase (ST). The differential expression of some genes was already reported in several solid tumors; however, several of them were found to be dysregulated in GBM for the first time. These data represent an important starting point to perform further orthogonal and functional validations to pinpoint the role of these glycogenes in GBM as diagnostic and therapeutic targets.
糖基化异常与肿瘤发生的多个过程有关，包括细胞信号转导、迁移和侵袭、免疫调节以及转移形成。糖缀合物的生物合成是通过协调和精细调节的酶反应来调节的。这包括糖基转移酶和糖苷酶的水平和活性、核苷酸糖代谢、底物可用性、表观遗传状态和细胞功能状态。胶质母细胞瘤 (GBM) 是最具侵袭性的脑肿瘤，常发生在成年人中，诊断后总体生存时间不超过 17 个月。GBM 已被世界卫生组织 (WHO) 归类为 4 级星形细胞瘤，并分为 G-CIMP、神经前型、经典型和间充质型亚型。已经阐明了与 GBM 侵袭性相关的几种生物分子特征；然而，需要更多的研究来阐明糖基化在 GBM 病理学中的作用，研究其作为癌症靶点的潜力。在这里，我们专注于 GBM 中涉及蛋白质 N-和 O-糖基化的基因改变。具体来说，使用来自公共存储库的星形细胞瘤-TCGA-RNAseq 数据集分析糖基因的 mRNA 水平。与神经前型和经典型亚型相比，在最具侵袭性的间充质型 GBM 中，共有 68 个基因差异表达，并且将这些基因的表达与正常脑组织进行比较。其中，我们重点关注 38 个基因，这些基因编码属于以下 10 种蛋白质的蛋白质：1）天冬酰胺糖基化 (ALG)；2）糖基转移酶 (B3T、B4T)；3）岩藻糖基转移酶 (FUT)；4）乙酰半乳糖胺基转移酶 (GALNT)；5）己糖胺酶 (HEX)；6）甘露糖苷酶 (MAN)；7）乙酰葡萄糖胺基转移酶 (MGAT)；8）唾液酸酶或神经氨酸酶 (NEU)；9）溶质载体 35 家族 (SLC)；和 10）唾液酸转移酶 (ST)。一些基因的差异表达已在几种实体肿瘤中报道；然而，其中一些基因在 GBM 中首次被发现失调。这些数据代表了进一步进行正交和功能验证的重要起点，以确定这些糖基因在 GBM 中的诊断和治疗靶点的作用。
