Glycosylation: A possible link between diet and stemness in intestinal cancer

糖基化：饮食与肠癌干性之间的可能联系

• 批准号: 385542443
• 负责人: Privatdozentin Dr. Melek Canan Arkan, Ph.D.
• 金额: --
• 依托单位: Institut für Biochemie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/385542443?language=en
• 关键词: Glycosylation; possible; link; between; diet

Current knowledge still lacks cause and effect of key processes that take place during malignant transformation in colorectal cancer (CRC). These are important not only for understanding the disease pathology in the intestine but also for designing realistic strategies to limit the mortality that it causes.Tumor cells display a wide range of glycosylation changes compared to non transformed tissue. Indeed, modifications in the glycosylation pattern appear as a hallmark of cancer. Glycosylation, the most commonly occurring posttranslational modification (PTM), plays a critical role in intercellular and intracellular processes that are fundamental to the development of multicellularity. In fact, PTMs are considered a dominant signature of pluripotency and stemness. A recent study suggests high fat diet (HFD) induced obesity augments the numbers and function of Lgr5+ intestinal stem cells and increases their capacity to initiate tumors in the intestine thus adding another layer of complexity over dietary cues in regulating intestinal tumor biology. Our current understanding of the controlling mechanisms that set the balance between stem cell self renewal and differentiation is extensively derived from genomic, transcriptomic, and epigenomic studies, and often undermines the functional significance of glycan chains, despite their high abundance in stem cell niche. An intricate association between glycosylation and stemness stands solid, although whether this would be a potential link between diet and cancer remains to be clarified. This proposal aims at unraveling whether glycan structure modifications are functionally involved in inducing tumor cell stemness during diet associated cancer. Given the ever increasing worldwide incidence of diet linked malignancies, defining a role for glycans during dedifferentiation in CRC is timely. Since glycosylation is a reversible modification and highly susceptible to environmental factors, characterizing glycans under a diet context can set the stage for early detection biomarkers and future drug discovery aimed at developing therapeutic interventions against intestinal cancer.

目前的知识仍然缺乏在结直肠癌（CRC）恶性转化过程中发生的关键过程的因果关系。这不仅对理解肠道疾病的病理学很重要，而且对设计现实的策略来限制它导致的死亡率也很重要。与未转化的组织相比，肿瘤细胞表现出广泛的糖基化变化。事实上，糖基化模式的改变似乎是癌症的一个标志。糖基化是最常见的翻译后修饰（PTM），在细胞间和细胞内过程中起着关键作用，是多细胞发育的基础。事实上，ptm被认为是多能性和干性的主要特征。最近的一项研究表明，高脂肪饮食（HFD）诱导的肥胖增加了Lgr5+肠道干细胞的数量和功能，并增加了它们在肠道中启动肿瘤的能力，从而在调节肠道肿瘤生物学方面增加了饮食线索的另一层复杂性。我们目前对设置干细胞自我更新和分化之间平衡的控制机制的理解主要来自基因组学、转录组学和表观基因组学的研究，并且经常破坏聚糖链的功能意义，尽管它们在干细胞生态位中含量很高。糖基化和干细胞之间的复杂联系是确凿的，尽管这是否会是饮食和癌症之间的潜在联系还有待澄清。本研究旨在揭示糖结构修饰是否在功能上参与饮食相关癌症诱导肿瘤细胞干性的过程。鉴于全球范围内与饮食相关的恶性肿瘤发病率不断上升，确定聚糖在结直肠癌去分化过程中的作用是及时的。由于糖基化是一种可逆的修饰，并且对环境因素非常敏感，因此在饮食背景下表征多糖可以为早期检测生物标志物和未来的药物发现奠定基础，旨在开发针对肠癌的治疗干预措施。