Aberrantly secreted glycoproteins as markers of liver cancer

异常分泌的糖蛋白作为肝癌的标志物

• 批准号: 8695094
• 负责人: Anand S. Mehta
• 金额: $ 31.18万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-08 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695094
• 关键词: AFP gene; Adult; Apical; Appearance; Bile fluid; Biliary; Biological; Biological Markers; Blood; Blood capillaries; Cell-Cell Adhesion; Cells; Cirrhosis; Defect; Development; Diagnostic Neoplasm Staging; Early Diagnosis; Epithelial Cells; Glycoproteins; Goals; Hepatocyte; Human; Knowledge; Lead; Link; Liver; Liver Cirrhosis; Logic; MDCK cell; Malignant Neoplasms; Malignant neoplasm of liver; Patients; Play; Polysaccharides; Primary carcinoma of the liver cells; Proteins; Proteome; Reporting; Role; Screening for cancer; Serum; Stream; Structure; Testing; Tissues; Tumor Tissue; Validation; Work; alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; base; bile duct; capillary; cohort; glycosylation; overexpression; trafficking; tumor progression

DESCRIPTION (provided by applicant): We, along with others, have shown increased levels of fucosylation with the development of hepatocellular carcinoma (HCC). In an effort to determine the origin of this increased fucosylation, we have performed N-linked glycan analysis of HCC tissue, the surrounding non tumor tissue, and compared this to tissue from a non-diseased adult liver. Surprisingly, no difference in the level of fucosylation was observed from the three donor groups, suggesting that the increased levels of fucosylation observed in the serum of those with HCC is not the result of increased synthesis of fucosylated proteins in the cancer tissue. In addition, the level of fucosylation observed in tissue was much higher than that observed on liver derived serum glycoproteins. On the other hand, increased levels of a tetra-antennary glycan were observed in the HCC tissue as compared to the surrounding tissue or to the non-diseased livers. Recent work by our collaborator has suggested that fucosylation controls the polarized secretion of glycoproteins and directs their secretion apically into the bil. Indeed, bile glycoforms are more heavily fucosylated than in serum and closely resemble those observed in the serum of HCC patients. It is our hypothesis that the over-expression of ¿ 1,6-N-acetylglucosaminyltransferase V (MGAT-5), which is responsible for the increased branching we have observed, leads to a loss of a tight blood-biliary barrier and the release of fucosylated proteins into the blood. This hypothesis, along with the use of this knowledge to find new biomarkers of HCC, will be tested in 3 aims. First we will examine the role of MGAT-5 in enforcing the polarized secretion of core fucosylated proteins. It is hypothesized that the overexpression of MGAT-5 that we observe in HCC tissue leads to a defect in the blood- biliary barrier and the aberrant release of fucosylated proteins into the blood. In specific aim 2 we will perform glycoproteomic analysis of bile for markers of HCC. The logic here is that all hepatocytes have the ability to secrete into the blood stream or into the bile capillaries, which eventually forms the bile ducts. Loss of hepatocyte polarity will lead to the aberrant appearance of fucosylated proteins in the blood. In specific Aim 3 we will examine the ability of our identifid biomarkers to differentiate patients with HCC from patients with liver cirrhosis in a cohort of 1500 patients. The ability of these markers to distinguish HCC from cirrhosis as compared to AFP and other potential biomarkers of HCC will be determined.

描述（由申请人提供）：我们和其他人一起发现岩藻糖基化水平随着肝细胞癌（HCC）的发展而增加。为了确定这种增加的岩藻糖基化的起源，我们进行了 N 连接聚糖分析。 HCC 组织，周围的非肿瘤组织，并将其与来自未患病成人肝脏的组织进行比较，令人惊讶的是，三个供体组中没有观察到岩藻糖基化水平的差异，这表明在肝癌患者的血清中观察到的岩藻糖基化水平增加并不是癌症组织中岩藻糖基化蛋白合成增加的结果。此外，在组织中观察到的岩藻糖基化水平远高于在肝脏来源的血清糖蛋白上观察到的水平。另一方面，与周围组织或未患病的肝脏相比，在 HCC 组织中观察到四触角聚糖水平增加，我们的合作者最近的工作表明岩藻糖基化控制着。事实上，胆汁糖型比血清中的岩藻糖基化程度更高，并且与 HCC 患者血清中观察到的非常相似，我们假设 ¿ 1,6-N-乙酰氨基葡萄糖转移酶 V (MGAT-5) 负责我们观察到的分支增加，导致紧密的血胆屏障丧失以及岩藻糖基化蛋白释放到血液中。利用这些知识寻找新的 HCC 生物标志物，我们将在 3 个目标中进行测试。首先，我们将检查 MGAT-5 在加强核心极化分泌中的作用。我们在 HCC 组织中观察到的 MGAT-5 过度表达导致血胆屏障缺陷以及岩藻糖基化蛋白异常释放到血液中。这里的逻辑是，所有肝细胞都有能力分泌到血流或胆汁毛细血管中，最终形成胆管损失。肝细胞极性的改变将导致血液中岩藻糖基化蛋白的异常。在具体目标 3 中，我们将检查我们鉴定的生物标志物在 1500 名患者的队列中区分 HCC 患者和肝硬化患者的能力。将确定与 AFP 和 HCC 的其他潜在生物标志物相比，区分 HCC 和肝硬化。