Glycosylation and Glycoproteins in Thyroid Cancer: A Potential Role for Diagnostics

Abstract

Glycosylation is the most common and the most diverse form of co-and post-translational modifications. An analysis of the Swiss-PROT database has led to the estimation that more than 50% of all proteins are glycosylated. Genes coding proteins involved in all types of oligosaccharides biosynthesis represent 0.5 to 1% of the translated genome (Dennis et al., 1999). Glycoproteins are found ubiquitously in an organism either as soluble (intracellular or extracellular) or as membrane bound molecules. There is a great structural variety of glycoproteins based on the type, length and linkage of a carbohydrate components as well as the degree of saturation of potential glycosylation sites on the protein itself. Carbohydrates can have a significant influence on the physicochemical properties of glycoproteins, affecting their folding, solubility, aggregation and degradation. Furthermore, glycan chains in glycoproteins play key roles in many biological processes such as embryonic development, immune response and cell-cell interactions in which sugar-sugar or sugar-protein specific recognition is involved (Wei & Li , 2009). Altered glycosylation is an universal feature of cancer cells, and certain glycan structures and glycoproteins are well-known tumor markers. These include for example glycoproteins such as carcinoembryonic antigen (CEA), commonly used as a marker of colorectal cancer, prostate-specific antigen (PSA) and CA-125 used in the diagnosis of ovarian cancer (Drake et al., 2010). High expression of some glycosyl epitopes for example sialyl Lewis a, sialyl Lewis x, Lewis y, promotes invasion and metastasis. Antibodies against Lewis antigens are used for evaluation of specimens from breast, bladder, colorectal, esophageal and lung carcinomas (Drake et al., 2010). Glycans can regulate different aspects of tumor progression, including proliferation, invasion and metastasis. Cancer-related changes in glycosylation can reflect disease specific alterations in glycan biosynthetic pathways. These include variations in the expression and activity of glycosyltransferases, enzymes that add monosaccharides to acceptors, i.e. proteins or growing carbohydrate chains and glycosidases which catalyze the hydrolysis of the glycosidic linkage to release sugars. There are three most common categories of protein glycosylation 1) N-glycosylation, where glycans are attached to asparagine residues in a consensus sequence N-X-S/T via N-acetylglucosamine (GlcNAc) residue; 2) O-glycosylation, where glycans are attached to serine or threonine via N-acetylgalactosamine (GalNAc) residue (mucin type glycosylation);

Glycosylation in the Thyroid Gland: Vital Aspects of Glycoprotein Function in Thyrocyte Physiology and Thyroid Disorders

“…In the case of O -GlcNAcylation, a single GlcNAc is added to the Ser or Thr residues ( Figure 1 ) [ 18 , 19 ]. O -GlcNAcylation is characteristic for cellular proteins, while most of the surface and secreted as well as some lysosomal proteins are subject to N - and O -glycosylation [ 13 , 20 , 21 ].…”

“…Glycans on thyroid proteins play significant roles in Tg transport and hormone synthesis [ 8 ], TSH activity [ 9 ] and TSH recognition by its receptor [ 6 ], as well as iodide transport via sodium/iodide symporter [ 23 ] and pendrin [ 24 ]. Proper glycosylation of proteins is crucial to the proper functioning of the thyroid gland; changes in GT expression and glycan structure contribute to thyroid disorders [ 21 , 25 ].…”

Glycosylation of thyroid-stimulating hormone receptor

“…N-glycans are crucial for the proper folding of TSHR protein, the receptor trafficking to the cell membrane, as well as the binding of TSH and TRAb produced in thyroid autoimmunity to TSHR [48]. It is well known that glycosylation plays a significant role in tumour progression, metastasis, and immune modulation of various types of cancers, including thyroid carcinomas [3,73]. The contribution of glycosylation changes to disease progress was shown also in autoimmunity processes [66], among others those taking place in the thyroid gland [72,75].…”

“…logicznej różnych typów nowotworów, w tym guzów tarczycy [3,73]. Udział zmian glikozylacji w postępie choroby wykazano również w procesach autoimmunizacyjnych [66], między innymi w gruczole tarczowym [72,75].…”

“…Glycosylated proteins (glycoproteins) are present in every tissue and cell of our body. It is estimated that more than half of all proteins contain bound oligosaccharides [2][3][4]. Thyroid-stimulating hormone receptor (TSHR) is one of the highly glycosylated membrane proteins.…”