ROLE OF SORD IN SUGAR-MEDIATED CANCER METASTASIS

SORD 在糖介导的癌症转移中的作用

基本信息

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
项目类别：
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

项目摘要

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 人死于结直肠癌。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，成人结直肠癌患者的死亡率一直在上升，原因不明。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原因。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中，SSB 是指用精制糖（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。流行病学研究表明，超过一半的美国成年人在某一天食用 SSB。 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，与肥胖无关的死亡率这个问题至关重要，因为某些结直肠癌患者经常出现这种情况。此外，美国的肿瘤学家和营养学家建议 CRC 患者饮用 SSB。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，这是一种培养基。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），其与山梨醇水平的增加相关。 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），并且 SORD 对于转移是必需的。值得注意的是，SORD 的缺失也是如此。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。我们认为，SORD 通过与糖相互作用在加速 CRC 转移中发挥关键作用。三个目标：目标 1：确定 SORD 如何加速 HFCS 条件下的 CRC 运动。 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。成功完成这些拟议的研究将使 SORD 成为一种治疗性小说。此外，我们的结果将确定可能起作用的代谢途径和代谢物。最后，我们的研究将强调 HFCS 的危险。消耗，特别是以SSB的形式，这可能会加速CRC转移，这将改变当前的情况。 CRC 患者的临床实践和饮食指南，显着降低 CRC 死亡率。