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）：该项目的目的是了解线粒体醛脱氢酶1B1（ALDH1B1）在乙醇诱导的结直肠癌发生中的作用。慢性酒精滥用引起了许多病理结果，包括对肝脏，大脑和其他器官（例如结肠癌）的损害。国际癌症研究机构（IARC）建立了饮酒与大肠癌之间的因果关系。几个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。负责饮酒的某些主要毒性作用的乙醇衍生的乙醛被醛脱氢酶（ALDHS）代谢为乙酸盐，主要是通过线粒体aldh2代谢，并且在较小程度上由细胞质Aldh1a1代谢。我们最近表明，ALDH1B1与AldH2共享72％相同的氨基酸序列，（A）对乙醛和视网膜醛具有高亲和力，并且（B）是潜在的生物标志物，并且参与了人类结直肠癌。总之，这些数据支持我们的新假设，即乙醛/视网膜醛代谢酶ALDH1B1是乙醇诱导的结直肠癌的关键参与者。因此，我们建议：1）通过使用ALDH1B1基因敲除小鼠并确定ALDH1B1在结直肠癌发展中的作用，并建立了用于乙醇诱导的结直肠癌的动物模型，以及2）2）阐明了AldH1B1作为饮酒诱导的人类癌症患者的肠道癌和非肠道癌症的生物癌的生物标志物作为生物标志物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（ALDH1B1）在小鼠和人类中乙醇诱导的大肠癌中的作用。最重要的是，这些研究有望验证使用ALDH1B1作为结肠癌的早期有效诊断标记，并作为预防或治疗乙醇诱导的结肠癌的治疗靶标，以及未来可能与其他酒精相关的癌症。