Glycomic and Glycoproteomic Analysis of Serum from Patients with Stomach Cancer Reveals Potential Markers Arising from Host Defense Response Mechanisms
Glycomic and Glycoproteomic Analysis of Serum from Patients with Stomach Cancer Reveals Potential Markers Arising from Host Defense Response Mechanisms
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DOI：
10.1021/pr101036b
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发表时间：
2011-03-01
影响因子：
4.4
通讯作者：
Rudd, Pauline M.
中科院分区：
文献类型：
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作者：
Bones, Jonathan;Byrne, Jennifer C.;Rudd, Pauline M.
尽管在发达国家胃癌的发病率降低，但由于疾病在早期阶段的无症状性质、随后的晚期诊断和低的5年生存率，胃癌的诊断仍然具有不良预后。内镜检查仍然是诊断胃癌的主要标准，目前的标志物，碳水化合物抗原19-9（CA 19 -9）缺乏所需的灵敏度和特异性水平，以使其在临床上用于诊断监测。因此，目前需要额外的标志物来提高胃癌早期诊断的准确性。总之，血清的糖组学、蛋白质组学和糖蛋白质组学分析具有鉴定这些可能的标志物的潜力。本文报告了一项发现性研究，使用了80例胃癌患者、10例良性胃病患者和20例匹配对照的术前血清。总血清和免疫亲和力耗尽血清的糖组学分析显示，三触角聚糖上存在的唾液酸刘易斯X表位（Sle（X））水平统计学显著增加，伴随IgG上存在的核心岩藻糖基化无半乳糖基双触角聚糖（称为IgG GO糖型）水平增加，这与疾病发病机制增加相关。使用2D-DiGE的蛋白质表达分析在耗尽的血清中返回了许多差异表达的蛋白质候选物，其中许多在随后的糖基化研究期间显示携带三触角SLe（X）。实验数据的生物学途径分析返回补体激活和急性期反应信号传导作为胃癌患者血清中最显著改变的途径。基于这些发现，提示IgG GO的表达增加和补体激活是对胃肿瘤存在的宿主应答，而Sle（X）和急性期应答蛋白的表达增加是致癌过程中促炎细胞因子信号传导（包括IL-6）的结果。本文提出的方法提供了对疾病的潜在机制的深入了解，并且糖组和糖蛋白组中所产生的变化提供了作为胃癌诊断和预后监测的潜在标志物的希望。
Despite the reduced incidence of gastric cancer in the developed world, a diagnosis of stomach carcinoma still carries a poor prognosis due to the asymptomatic nature of the disease in the early stages, subsequent advanced stage diagnosis, and a low 5 year survival rate. Endoscopy remains the primary standard for diagnosis of stomach carcinoma and the current marker, carbohydrate antigen 19-9 (CA19-9) lacks the levels of sensitivity and specificity required in order to make it clinically useful for diagnostic monitoring. Therefore, there is a current need for additional markers to improve the diagnostic accuracy for the early stages of stomach cancer. Together, glycomic, proteomic, and glycoproteomic analyses of serum have the potential to identify such probable markers. A discovery study is reported here using preoperative serum from 80 stomach cancer patients, 10 patients bearing benign stomach disease, and 20 matched controls. Glycomic analysis of the total and immunoaffinity depleted serum revealed statistically significant increases in the levels of sialyl Lewis X epitopes (SLe(X)) present on triantennary glycans accompanied by increased levels of core fucosylated agalactosyl biantennary glycans present on IgG (referred to as the IgG GO glycoform) which are associated with increasing disease pathogenesis. Protein expression analysis using 2D-DiGE returned a number of differentially expressed protein candidates in the depleted serum, many of which were shown to carry triantennary SLe(X) during subsequent glycornic investigations. Biological pathway analysis of the experimental data returned complement activation and acute phase response signaling as the most significantly altered pathways in the stomach cancer patient serum. Upon the basis of these findings, it is suggested that increased expression of IgG GO and complement activation are a host response to the presence of the stomach tumor while the increased expression of SLe(X) and acute phase response proteins is a result of pro-inflammatory cytokine signaling, including IL-6, during carcinogenesis. The approach presented herein provides an insight into the underlying mechanisms of disease and the resulting changes in the glycome and glycoproteome offer promise as potential markers for diagnosis and prognostic monitoring in stomach cancer.