Glycans in Hepatocellular Carcinoma

 描述(由申请人提供)：我们研究的目标是确定补充甲胎蛋白(AFP)及其核心岩藻糖基化类似物(AFP-L3)的血清学标志物，以检测可治疗阶段的肝细胞癌(HCC)。我们和其他人已经证明，蛋白N-糖型的主要再分布发生在肝硬变的癌前阶段。我们最新的研究表明，在肝细胞癌中，特定糖肽的高甘露糖、核心和外臂岩藻糖化糖形式增加。这些糖形式与肝脏分泌的糖蛋白有关，并可在血清中检测到。在这项研究中，我们通过新开发的LC-MS-MRM靶向定量方法分析了携带这些肝癌特异性N-糖链修饰的肝脏分泌糖蛋白。之所以这样做，是因为AFP和超声只能检测到大约60%的肝细胞癌病例，而且随着发病率的不断增加，需要额外的标志物来提高对这种恶性肿瘤的筛查敏感性。我们的数据表明，对特定糖蛋白多肽的特定糖形式进行量化可提供最高的诊断准确率。优化的糖苷酶辅助LC-MS-MRM方法首次允许对特定部位的糖肽标记候选进行有针对性的验证。确定临床适用的肝癌标志物对疾病管理和患者健康具有潜在的深远影响。我们的研究有望在蛋白质糖基化对癌症发生发展的功能影响方面产生新的假说，并激励癌症检测研究的新方向。

 DESCRIPTION (provided by applicant): The goal of our study is to identify serologic markers that complement alpha fetoprotein (AFP) and its core- fucosylated analog (AFP-L3) in the detection of hepatocellular carcinoma (HCC) at a treatable stage. We and others have shown that major re-distribution of protein N-glycoforms occurs at the premalignant stage of liver cirrhosis. Our latest studies show that high mannose, core- and outer arm- fucosylated glycoforms of specific glycopeptides increase in HCC. These glycoforms are associated with liver secreted glycoproteins and are detectable in serum. In this study, we analyze liver secreted glycoproteins carrying these HCC specific N- glycan modifications by newly developed LC-MS-MRM targeted quantification methods. This is done because AFP and ultrasonography detect only approximately 60% of HCC cases and additional markers are needed to improve sensitivity of screening for this malignancy with continuously increasing incidence. Our data suggests that quantification of specific glycoforms of specific glycoprotein peptides offers the highest diagnostic accuracy. The optimized glycosidase assisted LC-MS-MRM methods allow, for the first time, targeted validation of the site specific glycopeptide marker candidates. Defining clinically applicable markers of HCC has potentially far-reaching consequences for disease management and patient health. Our study is expected to generate new hypotheses on the functional impact of protein glycosylation on the development of cancer and to stimulate new line of cancer detection research.