ROLE OF SORD IN SUGAR-MEDIATED CANCER METASTASIS

在美国，结直肠癌(CRC)是癌症相关死亡的第二大原因。估计有53,200人 2020年将有人死于CRC。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，由于未知的原因，成年人数量一直在增加。结直肠癌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。这项提议旨在揭示潜在的 控制结直肠癌转移的机制以及导致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是任何用精制糖加甜的液体，如蔗糖和 高果糖玉米糖浆(HFCS)，两者都由葡萄糖和果糖组成，比例约为1：1。 在美国，超过一半的成年人在特定的一天消费SSB。流行病学研究表明， SSB的用量与晚期结直肠癌的复发和死亡率呈正相关。 然而，目前尚不清楚SSB摄入是否会直接影响晚期结直肠癌的转移， 因此，死亡率与肥胖无关。这个问题很关键，因为某些结直肠癌患者经常 消费SSB。此外，美国的肿瘤学家和营养学家建议他们的结直肠癌患者 能量饮料和浓缩果汁--事实上，这是添加了大量糖的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(以下称为HFCS条件)会增加血管的迁移和侵袭 结直肠癌细胞系(下称结直肠癌细胞株)，这与山梨醇水平的增加有关。删除以下内容 依赖NAD(H)的山梨醇脱氢酶(SORD)降低肾小球系膜细胞的CRC活力和山梨醇水平 条件。我们的异种移植小鼠模型也显示，HFCS治疗增加了结直肠癌转移(局部 侵袭和肝转移)，SORD是转移所必需的。值得注意的是，SORD的损失还 在高糖条件下抑制CRC运动，在高糖条件下，葡萄糖通过多元醇途径转化为果糖。 众所周知，长期摄入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结直肠癌转移中起关键作用。我们建议 三个目标：目标1：确定在HFCS条件下SORD如何加速CRC的运动。目标2：确定 SORD如何在高糖条件下增加结直肠癌的运动能力。目标3：了解SORD在《儿童权利公约》中的作用 转移。这些拟议研究的成功完成将使SORD成为一种新的治疗方法 结直肠癌转移的靶点。此外，我们的结果将确定代谢途径和代谢物可能有助于 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，可能会加速结直肠癌的转移。这将改变当前 为结直肠癌患者提供临床实践和饮食指南，显著降低结直肠癌死亡率。

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.