Abstract
Treatment of advanced and metastatic bladder carcinoma is often ineffective and displays variable clinical outcomes. Studying this aggressive molecular subtype of bladder carcinoma will lead to better understanding of the pathogenesis which may lead to the identification of new therapeutic strategies. The non-type bladder subtype is phenotypically mesenchymal and has mesenchymal features with a high metastatic ability. Post-translational addition of oligosaccharide residues is an important modification that influences cellular functions and contributes to disease pathology. Here, we report the comparative analysis of N-linked glycosylation across bladder cancer subtypes. To analyze the glycosite-containing peptides, we carried out LC-MS/MS-based quantitative proteomic and glycoproteomic profiling. We identified 1299 unique N-linked glycopeptides corresponding to 460 proteins. Additionally, we identified 118 unique N-linked glycopeptides corresponding to 84 proteins to be differentially glycosylated only in non-type subtypes as compared to luminal/basal subtypes. Most of the altered glycoproteins were also observed with changes in their global protein expression levels. However, alterations in 55 differentially expressed glycoproteins showed no significant change at the protein abundance level, representing that the glycosylation site occupancy was changed between the non-type subtype and luminal/basal subtypes. Importantly, the extracellular matrix organization pathway was dysregulated in the non-type subtype of bladder carcinoma. N-glycosylation modifications in the extracellular matrix organization proteins may be a contributing factor for the mesenchymal aggressive phenotype in non-type subtype. These aberrant protein glycosylation would provide additional avenues to employ glycan-based therapies and may lead to the identification of novel therapeutic targets.
Highlights
Bladder carcinoma is typically encountered in older patients [1] and found to be associated with significant mortality, morbidity and cost of treatment [2,3]
Understanding the molecular subtypes of bladder carcinoma is of pronounced significance as it can help in gaining knowledge on the disease pathogenesis and determining personalized therapy
N-acetylgalactosaminyltransferase 1 (GALNT1) overexpression has been reported for the aberrant glycosylation of integrin α3β1 which leads to the change in the conformation of integrin and further induces focal adhesion kinase (FAK) activation in bladder cancer cells [35]
Summary
Bladder carcinoma is typically encountered in older patients [1] and found to be associated with significant mortality, morbidity and cost of treatment [2,3]. Increasing high-throughput datasets have increased our knowledge and the understanding of cancer pathogenesis [4] This led to the identification of the molecular subtypes of bladder carcinoma; it still lacks the precision as well as in-depth clinical annotation [5]. It would be remarkable to correlate levels of N-linked glycosylation in bladder carcinoma molecular subtypes. We employed a liquid chromatography tandem-mass spectrometry (LC-MS/MS) based approach to investigate protein expressions and their glycosylation levels. To our knowledge, this is the first report on the profiling of the glycoproteins in bladder carcinoma and further dissection of it to check the glycosylation pattern across different subtypes
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