Glycans in Hepatocellular Carcinoma

 描述（由申请方提供）：我们研究的目的是鉴定在可治疗阶段检测肝细胞癌（HCC）中补充甲胎蛋白（AFP）及其核心岩藻糖基化类似物（AFP-L3）的血清学标志物。我们和其他人已经表明，蛋白质N-糖型的主要重新分布发生在肝硬化的癌前阶段。我们的最新研究表明，肝癌中特定糖肽的高甘露糖、核心和外臂岩藻糖基化糖型增加。这些糖型与肝脏分泌的糖蛋白相关，可在血清中检测到。在这项研究中，我们分析了肝脏分泌的糖蛋白携带这些肝癌特异性N-聚糖修饰的新开发的LC-MS-MRM靶向定量方法。之所以这样做，是因为AFP和超声检查仅检测到约60%的HCC病例，并且需要额外的标记物来提高筛查这种恶性肿瘤的灵敏度，其发病率不断增加。我们的数据表明，特定糖蛋白肽的特定糖型的定量提供了最高的诊断准确性。优化的糖苷酶辅助LC-MS-MRM方法首次允许对位点特异性糖肽标记候选物进行靶向验证。定义HCC的临床适用标志物对疾病管理和患者健康具有潜在的深远影响。我们的研究有望为蛋白质糖基化对癌症发展的功能影响提出新的假设，并刺激新的癌症检测研究。

 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.