The role of ALDH1B1 in ethanol metabolism and colon cancer

描述(申请人提供)：本项目的目标是了解线粒体乙醛脱氢酶1b1(ALDH1B1)在乙醇诱导的结直肠癌发生中的作用。长期酗酒会导致过多的病理后果，包括肝脏、大脑和其他器官，如结直肠的损害。国际癌症研究机构(IARC)已经确定了饮酒和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。乙醇的大部分病理效应归因于其反应性代谢产物。乙醇产生的乙醛是酒精消费的一些主要毒性影响，由乙醛脱氢酶(ALDHs)代谢成乙酸酯，主要由线粒体ALDH2代谢，少量由胞质ALDH1A1代谢。我们最近发现，ALDH1B1与ALDH2有72%的氨基酸序列相同，(A)对乙醛和视黄醛有很高的亲和力，(B)是一个潜在的生物标志物和人类结直肠癌的参与者。总之，这些数据支持我们的新假设，即乙醛/视黄醛代谢酶ALDH1B1在乙醇诱导的结直肠癌的发展中起关键作用。因此，我们建议：1)通过使用Aldh1b1基因敲除小鼠和建立乙醇诱导的结直肠癌动物模型，确定ALDH1B1在结直肠癌发生中的作用；2)通过对酒精和非酒精患者的结直肠癌样本的免疫组织化学分析，阐明ALDH1B1作为酒精诱导的人类结直肠癌的生物标志物的作用。这些研究的结果将首次揭示第二线粒体ALDH(ALDH1B1)在乙醇诱导的小鼠和人类结直肠癌中的作用。最重要的是，这些研究有望验证ALDH1B1作为结肠癌的早期有效诊断标记物的使用，以及作为预防或治疗乙醇诱导的结肠癌以及未来可能与酒精相关的其他癌症的治疗靶点。

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.