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: 10684531
• 负责人: Jihye Yun
• 金额: $ 37.64万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684531
• 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 到 2020 年，人们将死于结直肠癌。另一个令人不安的事实是，年轻人的发病率和死亡率 自 20 世纪 90 年代以来，成年人的数量一直在增加，原因不明。 CRC患者的死亡率主要是 归因于肿瘤转移，这是一个复杂的、多步骤的过程。该提案旨在揭示潜在的 控制结直肠癌转移的机制以及导致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（例如蔗糖和蔗糖）增甜的任何液体。 高果糖玉米糖浆 (HFCS)，两者均由比例约为 1:1 的葡萄糖和果糖组成。 超过一半的美国成年人在某一天食用 SSB。流行病学研究表明 SSB 消耗量与晚期 CRC 的复发和死亡率呈正相关。 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 消耗 SSB。此外，美国的肿瘤学家和营养学家建议他们的结直肠癌患者饮用 能量饮料和浓缩果汁——实际上是添加大量糖的 SSB——因为 这些 SSB 还含有卡路里、蛋白质和/或微量营养素。我们的初步数据表明，介质 同时含有葡萄糖和果糖（以下简称 HFCS 条件）会增加 CRC 细胞系（以下简称 CRC 运动性），与山梨醇水平升高相关。的删除 NAD(H) 依赖性山梨醇脱氢酶 (SORD) 降低了 HFCS 中的 CRC 运动性和山梨醇水平 健康）状况。我们的异种移植小鼠模型还表明，HFCS 治疗增加了 CRC 转移（局部 侵袭和肝转移），SORD是转移所必需的。值得注意的是，SORD 的丢失也 在高葡萄糖条件下抑制 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 转移中发挥关键作用。我们建议 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 如何在高血糖条件下增加 CRC 运动性。目标 3：了解 SORD 在 CRC 中的作用 转移。这些拟议研究的成功完成将使 SORD 成为一种新型治疗方法 CRC转移的靶点。此外，我们的结果将确定可能有助于的代谢途径和代谢物 作为预防结直肠癌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 消耗，特别是以SSB的形式，可能会加速CRC转移。这将改变当前 CRC 患者的临床实践和饮食指南，显着降低 CRC 死亡率。