Glycosylation-dependent mechanisms regulating ovarian tumor cell phenotype

项目摘要/摘要 异常的表面糖基化是众所周知的肿瘤生物标志物，然而肿瘤的功能作用 糖苷在调节肿瘤细胞表型中的作用仍然知之甚少。α2-6唾液酸(一种体积大，负- 荷糖)是ST6Gal-I糖基转移酶所阐述的一种重要的肿瘤相关糖链。 我们小组的研究表明，ST6Gal-I唾液酸类化合物选择膜受体，包括TNFR1， 进而导致NF-κB的激活，ST6Gal-I在卵巢癌(OC)中普遍上调， 高表达水平与患者较差的生存和转移有关。此外，强制ST6Gal-I 在多种动物模型中的过度表达促进了肿瘤的发生和发展。的中心假说 目前的观点是，ST6Gal-I活性通过促进依赖的核因子-kB而促进OC的发育 向肿瘤细胞赋予癌症干细胞(CSC)样特征的信号事件。核因子-kB轴是 是CSCs中最活跃的通路，也是CSC表型的公认驱动因素。这个 肿瘤细胞唾液酸化调控NFkB信号和CSC行为的概念提出了一个新的概念 癌细胞生物学中的范例。拟议的研究有两个主要目标。第一个(目标1)是 确定主要干细胞转录因子Sox2是ST6Gal-I上调的关键诱导物 OC。我们的初步数据表明，Sox2直接与ST6Gal-I启动子结合来刺激转录。 在ST6Gal-I上调的下游，我们假设ST6Gal-I介导的受体唾液酸化指导 CSC通过NFkB重新编程，从而促进肿瘤的启动。的第二个主要目标 提案(目标2)是定义ST6Gal-I在卵巢癌腹膜扩散中的作用，这是主要的 患者死亡率的贡献者。与大多数实体肿瘤不同，OC主要通过液体流动传播 穿过腹膜腔，而不是通过血管或淋巴管。腹膜 具有非常低的氧分压，因此OC细胞对低氧的适应是OC的一个重要因素 进步。我们小组最近的研究表明，ST6Gal-I活性有助于预防 低氧通过增强HIF1α信号转导。目标2将测试ST6Gal-I介导的缺氧的前提 适应对于OC细胞在腹膜肿瘤微环境中的生存和扩张至关重要。 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 在卵巢癌发展和进展的早期和晚期发挥重要作用的机制。

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.