Glycosylation-dependent mechanisms regulating ovarian tumor cell phenotype

糖基化依赖性调节卵巢肿瘤细胞表型的机制

• 批准号: 10376286
• 负责人: Susan L Bellis
• 金额: $ 31.11万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376286
• 关键词: Animal Model; Area; Ascites; Binding; Biological Assay; Cancer Model; Cancer Patient; Cancer cell line; Carcinomatosis; Cell Respiration; Cell Survival; Cells; Cellular biology; Characteristics; Charge; Chemoresistance; Colon; Data; Development; Disease; Elements; Epithelial; Event; Fostering; Genes; Genetic Transcription; Genetically Engineered Mouse; Genus Hippocampus; Glycobiology; Glycolysis; Goals; Greater sac of peritoneum; Growth; HIF1A gene; Hypoxia; Implant; Knock-out; Knowledge; Link; Lymphatic; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Membrane; Mesenchymal; Messenger RNA; Metabolic; Metabolism; Minor; Molecular; Monitor; Mus; NF-kappa B; Neoplasm Metastasis; Neoplasms; Organoids; Ovarian; Oxygen; Pancreas; Pathway interactions; Patients; Peritoneal; Peritoneum; Phenotype; Play; Polysaccharides; Primary Neoplasm; Process; Property; Proteins; Reporting; Research; Role; ST6Gal I; Seminal; Sialic Acids; Signal Transduction; Solid Neoplasm; Structure; Surface; TNFRSF1A gene; Testing; Therapeutic Intervention; Tumor Markers; Up-Regulation; anticancer research; cancer cell; cancer stem cell; carcinogenesis; cell behavior; cohort; empowered; fluid flow; glucose uptake; glycosylation; glycosyltransferase; implantation; in vivo; innovation; mortality; neoplastic cell; novel; ovarian neoplasm; overexpression; peritoneal cancer; promoter; protein expression; protein function; receptor; sialylation; stem; stem cell biomarkers; stem cells; stem-like cell; sugar; transcription factor; tumor; tumor initiation; tumor metabolism; tumor microenvironment; tumor progression

Project Summary/Abstract Aberrant surface glycosylation is a well-known tumor biomarker, however the functional role of the tumor glycome in regulating tumor cell phenotype remains poorly-understood. α2-6 sialic acid (a bulky, negatively- charged sugar) is a prominent tumor-associated glycan elaborated by the ST6Gal-I glycosyltransferase. Research from our group has shown that ST6Gal-I sialylates select membrane receptors, including TNFR1, which in turn causes activation of NF-κB. ST6Gal-I is pervasively upregulated in ovarian cancer (OC), and high expression levels correlate with poor patient survival and metastasis. Furthermore, forced ST6Gal-I overexpression in multiple animal models fosters tumor initiation and progression. The central hypothesis of the current proposal is that ST6Gal-I activity contributes to OC development by promoting NF-kB-dependent signaling events that confer cancer stem cell (CSC)-like features to tumor cells. The NF-kB axis is one of the most hyperactivated pathways in CSCs, and is a well-accepted driver of the CSC phenotype. The concept that NFkB signaling and CSC behavior are regulated by tumor cell sialylation advances a new paradigm in cancer cell biology. The proposed research has two principal objectives. The first (Aim 1) is to establish that the master stem cell transcription factor, Sox2, is a key inducer of ST6Gal-I upregulation in OC. Our preliminary data show that Sox2 binds directly to the ST6Gal-I promoter to stimulate transcription. Downstream of ST6Gal-I upregulation, we postulate that ST6Gal-I-mediated receptor sialylation directs CSC reprogramming via NFkB, consequently facilitating tumor initiation. The second major goal of the proposal (Aim 2) is to define ST6Gal-I’s role in OC peritoneal dissemination, which is one of the chief contributors to patient mortality. Unlike most solid tumors, OC primarily disseminates via fluid flow throughout the peritoneal cavity rather than transit through the vasculature or lymphatics. The peritoneum has very low oxygen tension, and therefore OC cell adaptation to hypoxia is an essential element in OC progression. Recent studies from our group have shown that ST6Gal-I activity facilitates protection against hypoxia by potentiating HIF1α signaling. Aim 2 will test that premise that ST6Gal-I-mediated hypoxia adaptation is critical for OC cell survival and expansion within the peritoneal tumor microenvironment. Collectively, the proposed studies are expected to uncover a highly novel glycosylation-dependent mechanism that plays seminal roles in both early and late stages of OC development and progression.

项目总结/摘要 异常的表面糖基化是一种众所周知的肿瘤生物标志物，然而， 糖组在调节肿瘤细胞表型中的作用仍然知之甚少。α2-6唾液酸（一种大体积的负- 带电荷的糖）是由ST 6 Gal-I糖基转移酶加工的突出的肿瘤相关聚糖。 我们小组的研究表明，ST 6 Gal-I唾液酸化物选择膜受体，包括TNFR 1， 进而导致NF-κB活化。ST 6 Gal-I在卵巢癌（OC）中普遍上调，并且 高表达水平与患者存活和转移差相关。此外，强制ST 6 Gal-I 在多种动物模型中的过表达促进肿瘤的发生和发展。的中心假设 目前的建议是，ST 6 Gal-I活性通过促进NF-kB依赖性 肿瘤干细胞（CSC）是肿瘤干细胞（CSC）的一个重要组成部分。NF-kB轴是 是CSC中最过度活化的途径，并且是CSC表型的公认驱动因素。的 NFkB信号传导和CSC行为受肿瘤细胞唾液酸化调节的概念提出了一个新的观点， 癌症细胞生物学的典范。拟议的研究有两个主要目标。第一个（目标1）是 确定了主干细胞转录因子Sox 2是ST 6 Gal-I上调的关键诱导剂， OC.我们的初步数据表明，Sox 2直接结合到ST 6 Gal-I启动子，以刺激转录。 在ST 6 Gal-I上调的下游，我们假设ST 6 Gal-I介导的受体唾液酸化指导了 CSC通过NFkB重编程，从而促进肿瘤起始。第二个主要目标 目的2是确定ST 6 Gal-I在OC腹膜播散中的作用，这是研究OC腹膜播散的主要目的之一。 患者死亡率的贡献者。与大多数实体瘤不同，OC主要通过液体流动传播 而不是通过脉管系统或腹膜腔。腹膜 具有非常低的氧张力，因此OC细胞对缺氧的适应是OC的重要因素 进展我们小组最近的研究表明，ST 6 Gal-I活性有助于保护免受 通过增强HIF 1 α信号传导而缺氧。目的2将检验ST 6 Gal-I介导的缺氧 适应对于OC细胞在腹膜肿瘤微环境中的存活和扩增是至关重要的。 总的来说，拟议的研究有望揭示一种高度新颖的糖基化依赖性 在OC发育和进展的早期和晚期阶段都起着重要作用的机制。