ROLE OF SORD IN SUGAR-MEDIATED CANCER METASTASIS

SORD 在糖介导的癌症转移中的作用

• 批准号: 10446420
• 负责人: Jihye Yun
• 金额: $ 3.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-08 至 2022-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10446420
• 关键词: Acute; Address; Adenosine; Adult; Affect; Biological Markers; Biological Specimen database; Blood; Calories; Cancer Etiology; Cause of Death; Cessation of life; Chronic; Clinical Practice Guideline; Colorectal Cancer; Complex; Consumption; Data; Developed Countries; Development; Diabetes Mellitus; Diet; Dietary Factors; Dipeptidyl Peptidases; Distant Metastasis; Environmental Risk Factor; Enzymes; Fructose; Genetic; Glucose; Hyperglycemia; Incidence; Isotopes; Juice; L-Iditol 2-Dehydrogenase; Link; Liquid substance; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Liver; Micronutrients; Molecular; NADH; Neoplasm Metastasis; Nutritionist; Obesity; Oncologist; Organoids; Outcome; Pathway interactions; Patients; Persons; Phenotype; Play; Pre-Clinical Model; Process; Proteins; Reaction; Recurrence; Role; Sorbitol; Specimen; Sucrose; Survival Rate; Testing; Xenograft Model; Xenograft procedure; base; cancer cell; cell growth; cell motility; clinical practice; colon cancer cell line; colon cancer patients; colorectal cancer metastasis; colorectal cancer prevention; dietary guidelines; epidemiology study; experimental study; in vivo; migration; mortality; mouse model; new therapeutic target; polyol; protein expression; response; sugar; sweetened beverage; tool; tumor; young adult

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the USA. An estimated 53,200 people will die from CRC in 2020. Another disturbing fact is that the rates of incidence and mortality from young adults have been increasing since the 1990s for unknown reasons. The mortality of CRC patients is mainly attributed to tumor metastasis, a complex, multistep process. This proposal aims to uncover the underlying mechanisms that control CRC metastasis and the key pathways and environmental factors that contribute to it. One possible factor is sugar-sweetened beverages (SSBs), the consumption of which has dramatically increased in the past four decades. SSBs are any liquids that are sweetened with refined sugars, such as sucrose and high-fructose corn syrup (HFCS), both of which consist of glucose and fructose in a ratio of approximately 1:1. More than half of the adults in the USA consume SSBs on a given day. Epidemiological studies have shown a positive correlation between SSBs consumption and the recurrence of and mortality from advanced-stage CRC. However, it is still unclear whether SSB consumption can directly affect metastasis on advanced-stage CRC and, therefore mortality, independently of obesity. This question is critical because certain CRC patients regularly consume SSBs. Moreover, oncologists and nutritionists in the US recommend that their CRC patients drink energy drinks and concentrated juices—which are, in fact, SSBs with high amounts of added sugar—because these SSBs also contain calories, protein, and/or micronutrients. Our preliminary data show that a medium containing both glucose and fructose (hereafter, the HFCS condition) increased the migration and invasion of CRC cell lines (hereafter, CRC motility), which was correlated with an increased level of sorbitol. The deletion of a NAD(H)-dependent sorbitol dehydrogenase (SORD) decreased CRC motility and sorbitol level in the HFCS condition. Our xenograft mice models also showed that HFCS treatment increased CRC metastasis (local invasion and liver metastasis), and SORD was necessary for the metastasis. Notably, the loss of SORD also inhibited CRC motility in the high-glucose condition, in which glucose converts to fructose via the polyol pathway. It is known that chronic consumption of SSBs causes a high concentration of glucose in the blood. Thus, we hypothesize that SORD plays a key role in accelerating CRC metastasis by interacting with sugars. We propose three aims: Aim 1: Determine how SORD accelerates CRC motility in the HFCS condition. Aim 2: Determine how SORD increases CRC motility in the high-glucose condition. Aim 3: Understand the role of SORD in CRC metastasis. Successful completion of these proposed studies will characterize SORD as a novel therapeutic target for CRC metastasis. Further, our results will identify metabolic pathways and metabolites that may serve as new biomarkers or targets for preventing CRC metastasis. Finally, our study will highlight the danger of HFCS consumption, especially in the form of SSBs, which may accelerate CRC metastasis. This will change current clinical practices and dietary guidelines for CRC patients, significantly reducing CRC mortality.

结直肠癌（CRC）是美国癌症相关死亡的第二大原因。估计有53，200人 2020年将有100人死于CRC。另一个令人不安的事实是， 自1990年代以来，成年人人数一直在增加，原因不明。CRC患者的死亡率主要是 肿瘤转移是一个复杂的多步骤过程。该提案旨在揭示潜在的 控制结直肠癌转移的机制以及促成其转移的关键途径和环境因素。 一个可能的因素是含糖饮料（SSB），其消费量急剧增加 在过去的四十年里。SSB是用精制糖（如蔗糖）增甜的任何液体， 高果糖玉米糖浆（HFCS），两者均由葡萄糖和果糖以约1：1的比例组成。 超过一半的美国成年人在特定的一天消费SSB。流行病学研究表明， SSB消耗与晚期CRC的复发和死亡率之间正相关。 然而，目前尚不清楚SSB消耗是否会直接影响晚期CRC的转移， 因此死亡率与肥胖无关。这个问题很关键，因为某些CRC患者经常 消费SSB。此外，美国的肿瘤学家和营养学家建议他们的CRC患者饮用 能量饮料和浓缩果汁-事实上，它们是添加了大量糖的SSB-因为 这些SSB还含有卡路里、蛋白质和/或微量营养素。我们的初步数据显示 同时含有葡萄糖和果糖（以下简称HFCS条件）的细胞， CRC细胞系（下文称为CRC运动性），这与山梨醇水平升高相关。删除 a NAD（H）依赖性山梨醇脱氢酶（SORD）降低HFCS中CRC运动性和山梨醇水平 条件我们的异种移植小鼠模型也显示HFCS治疗增加了CRC转移（局部转移）， SORD是肿瘤转移所必需的。值得注意的是，SORD的损失也 在高糖条件下抑制CRC运动，其中葡萄糖通过多元醇途径转化为果糖。 众所周知，长期食用SSB会导致血液中葡萄糖浓度升高。因此我们 假设SORD通过与糖相互作用在加速CRC转移中起关键作用。我们提出 三个目标：目标1：确定SORD如何在HFCS条件下加速CRC运动。目标2：确定 SORD如何在高糖条件下增加CRC运动性。目标3：了解SORD在CRC中的作用 转移成功完成这些拟议的研究将使SORD成为一种新的治疗方法 靶向CRC转移。此外，我们的研究结果将确定代谢途径和代谢物， 作为预防CRC转移的新生物标志物或靶点。最后，我们的研究将强调HFCS的危险性 消耗，特别是以SSB的形式，这可能加速CRC转移。这将改变当前 临床实践和CRC患者的饮食指南，显著降低CRC死亡率。