The role of ALDH1B1 in ethanol metabolism and colon cancer

项目描述（由申请人提供）：本项目旨在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。慢性酒精滥用会导致大量的病理结果，包括对肝脏、大脑和其他器官（如结直肠）的损害。国际癌症研究机构（IARC）已经确定了饮酒与结直肠癌之间的因果关系。几项荟萃分析表明，饮酒与结直肠癌之间存在线性关系。乙醇的大部分病理作用归因于其活性代谢产物。乙醇衍生的乙醛，负责饮酒的一些主要毒性作用，被醛脱氢酶（ALDHs）代谢为醋酸盐，主要是通过线粒体ALDH2，在较小程度上通过细胞质ALDH1A1。我们最近表明，ALDH1B1与ALDH2具有72%相同的氨基酸序列，(a)对乙醛和视黄醛具有高亲和力，(b)是人类结直肠癌的潜在生物标志物和参与者。总之，这些数据支持了我们的新假设，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，我们提出：1)通过ALDH1B1敲除小鼠和建立的乙醇诱导的结直肠癌动物模型，确定ALDH1B1在结直肠癌发展中的作用；2)通过对酒精和非酒精患者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描述第二线粒体ALDH （ALDH1B1）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ALDH1B1作为结肠癌的早期有效诊断标志物的使用，并作为预防或治疗乙醇诱导的结肠癌以及未来潜在的其他酒精相关癌症的治疗靶点。

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.