The role of ALDH1B1 in ethanol metabolism and colon cancer

ALDH1B1 在乙醇代谢和结肠癌中的作用

• 批准号: 8704693
• 负责人: VASILIS VASILIOU
• 金额: $ 43.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704693
• 关键词: Acetaldehyde; Acetates; Affinity; Alcohol abuse; Alcohol consumption; Alcohol dehydrogenase; Alcohols; Amino Acid Sequence; Amino Acids; Animal Model; Asians; Biological Markers; Brain; Cancer cell line; Cancerous; Carcinogens; Caucasians; Caucasoid Race; Chronic; Colon; Colon Carcinoma; Colorado; Colorectal; Colorectal Cancer; Cytochrome P-450 CYP2E1; Data; Development; Diagnostic; Enzymes; Esophagus; Ethanol; Ethanol Metabolism; Ethanol toxicity; Family; Flushing; Future; Genetic Polymorphism; Genotype; Germany; Goals; Head and neck structure; Health; Heterozygote; Homozygote; Human; Hypersensitivity; Immunohistochemistry; Individual; International; International Agency for Research on Cancer; Investigation; Japan; Knockout Mice; Knowledge; Large Intestine; Link; Liver; Malignant Neoplasms; Measures; Meta-Analysis; Metabolism; Michigan; Mitochondria; Modeling; Molecular Biology; Mus; North Carolina; Oncogenes; Organ; Outcome; Pancreas; Participant; Patients; Population; Predisposition; Prevention; Proteins; Reaction; Relative (related person); Reporting; Retinaldehyde; Risk; Role; SW480; Saliva; Sampling; Signal Transduction; Stem cells; Syndrome; Time; Tissue Sample; Toxic effect; Tretinoin; Universities; Work; Xenograft Model; alcohol effect; aldehyde dehydrogenases; base; c-Myc Staining Method; cancer cell; carcinogenesis; catalase; colorectal cancer prevention; drinking; in vivo; mRNA Expression; member; non-alcoholic; novel; oxidation; problem drinker; promoter; small hairpin RNA; stem cell population; therapeutic target; transcriptome sequencing; tumor growth

DESCRIPTION (provided by applicant): The goal of this project is to understand the role of mitochondrial aldehyde dehydrogenase 1B1 (ALDH1B1) in ethanol- induced colorectal carcinogenesis. Chronic alcohol abuse elicits a plethora of pathological outcomes including damage to the liver, brain and other organs, such as the colorectum. A causal relationship between alcohol consumption and colorectal cancer has been established by the International Agency for Research on Cancer (IARC). Several meta-analyses suggest a linear relationship between alcohol consumption and colorectal cancer. Most of the pathological effects of ethanol are attributed to its reactive metabolites. Ethanol-derived acetaldehyde, responsible for some of the major toxic effects of alcohol consumption, is metabolized to acetate by aldehyde dehydrogenases (ALDHs), mostly by mitochondrial ALDH2 and, to a lesser extent, by cytosolic ALDH1A1. We have recently shown that ALDH1B1, which shares a 72% identical amino acid sequence with ALDH2, (a) has a high affinity for acetaldehyde and retinaldehyde, and (b) is a potential biomarker and participant in human colorectal cancer. Together, these data support our novel hypothesis that acetaldehyde/retinaldehyde- metabolizing enzyme ALDH1B1 is a key player in the development of ethanol-induced colorectal cancer. We therefore propose to: 1) determine the role of ALDH1B1 in colorectal cancer development by using Aldh1b1 knockout mice and established animal models for ethanol-induced colorectal cancer, and 2) elucidate the role of ALDH1B1 as a biomarker for alcohol-induced colorectal cancer in humans by immunohistochemical analysis of colorectal cancer samples from alcoholic and non-alcoholic patients. Findings from these investigations will, for the first time, delineate the role of the second mitochondrial ALDH (ALDH1B1) in ethanol-induced colorectal cancer in both mice and humans. Most importantly, these studies are expected to validate the use of ALDH1B1 as an early and effective diagnostic marker for colon cancer and as a therapeutic target for the prevention or treatment of ethanol-induced colon cancer, and potentially other alcohol-related cancers in the future.

描述（由申请人提供）：本项目的目的是了解线粒体醛脱氢酶1B 1（ALDH 1B 1）在乙醇诱导的结直肠癌发生中的作用。慢性酒精滥用会导致过多的病理结果，包括对肝脏、大脑和其他器官（如结肠直肠）的损害。国际癌症研究机构（IARC）已经确定了饮酒与结直肠癌之间的因果关系。一些荟萃分析表明，饮酒与结直肠癌之间存在线性关系。乙醇的大多数病理作用归因于其反应性代谢产物。乙醇衍生的乙醛，负责酒精消费的一些主要毒性作用，通过乙醛脱氢酶（ALDH）代谢为乙酸盐，主要是通过线粒体ALDH 2，在较小程度上，通过胞质ALDH 1A 1。我们最近发现，ALDH 1B 1与ALDH 2共享72%相同的氨基酸序列，（a）对乙醛和视黄醇具有高亲和力，（B）是人类结直肠癌的潜在生物标志物和参与者。总之，这些数据支持我们的新假设，即乙醛/视黄醇代谢酶ALDH 1B 1是乙醇诱导的结直肠癌发展的关键因素。因此，我们建议：1）通过使用Aldh 1b 1敲除小鼠和建立的乙醇诱导的结肠直肠癌动物模型来确定ALDH 1B 1在结肠直肠癌发展中的作用，以及2）通过对来自酒精和非酒精患者的结肠直肠癌样品的免疫组织化学分析来阐明ALDH 1B 1作为人类中酒精诱导的结肠直肠癌的生物标志物的作用。这些研究的结果将首次描述第二个线粒体ALDH（ALDH 1B 1）在小鼠和人类乙醇诱导的结直肠癌中的作用。最重要的是，这些研究有望验证ALDH 1B 1作为结肠癌早期有效诊断标志物的用途，并作为预防或治疗乙醇诱导的结肠癌的治疗靶点，以及未来可能的其他酒精相关癌症。