Deb Barnali, Patel Krishna, Sathe Gajanan, Kumar Prashant
Institute of Bioinformatics, International Technology Park, Bangalore 560066, India.
Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India.
J Clin Med. 2019 Aug 24;8(9):1303. doi: 10.3390/jcm8091303.
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.
晚期和转移性膀胱癌的治疗往往效果不佳，临床结果也各不相同。研究这种侵袭性的膀胱癌分子亚型将有助于更好地理解其发病机制，进而可能发现新的治疗策略。非典型膀胱亚型在表型上具有间充质特征，且具有较高的转移能力。寡糖残基的翻译后添加是一种重要的修饰，它影响细胞功能并导致疾病病理变化。在此，我们报告了膀胱癌各亚型间N-糖基化的比较分析。为了分析含糖基化位点的肽段，我们进行了基于液相色谱-串联质谱的定量蛋白质组学和糖蛋白质组学分析。我们鉴定出了对应于460种蛋白质的1299个独特的N-连接糖肽。此外，我们还鉴定出了对应于84种蛋白质的118个独特的N-连接糖肽，它们仅在非典型亚型中与管腔/基底亚型相比存在差异糖基化。大多数糖蛋白的改变也伴随着其整体蛋白表达水平的变化。然而，55种差异表达糖蛋白的改变在蛋白质丰度水平上没有显著变化，这表明非典型亚型和管腔/基底亚型之间糖基化位点占有率发生了改变。重要的是，细胞外基质组织途径在非典型膀胱癌亚型中失调。细胞外基质组织蛋白中的N-糖基化修饰可能是导致非典型亚型间充质侵袭性表型的一个因素。这些异常的蛋白质糖基化将为基于聚糖的治疗提供更多途径，并可能导致发现新的治疗靶点。
