Role of the Gut Microbiota and TLR4 in Alcoholic Hepatocarcinogenesis

肠道菌群和 TLR4 在酒精性肝癌发生中的作用

• 批准号: 8527630
• 负责人: Robert F. Schwabe
• 金额: $ 37.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527630
• 关键词: Alcoholic Liver Diseases; Alcohols; Antibiotics; Bone Marrow; Cancer Etiology; Candidate Disease Gene; Carcinogens; Cause of Death; Cells; Cessation of life; Chronic; Consumption; Data; Development; Diet; Diethylnitrosamine; Disease; Dose; Foundations; Gene Expression; Genes; Germ-Free; Goals; Hepatic; Hepatic Stellate Cell; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; Human; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-1; Interleukin-17; Interleukin-6; Intestines; Knock-out; Knockout Mice; Kupffer Cells; Lead; Ligands; Lipopolysaccharides; Liver; Liver diseases; MAPK8 gene; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Myeloid Cells; NF-kappa B; Neomycin; Pathway interactions; Patients; Play; Population; Prevention; Primary Prevention; Primary carcinoma of the liver cells; Risk; Risk Factors; Role; Secondary Prevention; Signal Transduction; Staging; TLR4 gene; TNF gene; Testing; Therapeutic Intervention; Tumor Necrosis Factor-Beta; Tumor Promotion; Wild Type Mouse; Wound Healing; base; carcinogenesis; cell type; cytokine; gut microbiota; mortality; new therapeutic target; non-alcoholic; non-alcoholic fatty liver; novel therapeutics; prevent; problem drinker; promoter; rifaximin; therapeutic target; toll-like receptor 4; treatment strategy; tumor; tumor initiation

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fifth most common cancer causing about 500,000 deaths/year world-wide. In the US, the incidence of HCC has almost doubled over the last three decades. Despite increases in HCV- and non-alcoholic fatty liver disease-induced HCC, alcohol is still considered a leading risk factor for the development of HCC. It is well established that (i) LPS levels are highly elevated in all stages of alcoholic liver disease (ALD), and that (ii) inflammation and injury in early stages of ALD are largely mediated by lipopolysaccharide (LPS) and its receptor TLR4. Recently, inflammatory pathways such as NF-kB, IL-1, IL-6 and lymphotoxin α and ß have been identified as key contributors to non-alcoholic hepatocarcinogenesis. We hypothesize that inflammatory signals play an essential role in alcoholic hepatocarcinogenesis, and that LPS and TLR4 act as key promoters of inflammation-driven proliferation and hepatocarcinogenesis in ALD. We hypothesize that LPS and TLR4 represent the most upstream regulators of inflammatory procarcinogenic signaling cascades such as NF-kB, JNK, IL-1, IL-6, IL-17, lymphotoxin α and ß. The long-term goal of this application is to establish LPS and TLR4 as key contributors to an inflammatory gut-liver axis that promotes alcoholic hepatocarcinogenesis, and to develop new concepts for the prevention or treatment of alcoholic HCC. The role of TLR4 in alcoholic hepatocarcinogenesis will be tested in TLR4ko and wt mice subjected to a priming dose of diethylnitrosamine (DEN) and subsequent alcohol-containing diets (AIM 1). The contribution of the gut microbiota to alcoholic HCC will be assessed gut-sterilized and germ-free mice treated with DEN and alcohol-containing diets (AIM 2). Target cells and molecular mechanisms by which LPS and TLR4 promote alcoholic HCC will be determined in bone marrow-chimeric mice and mice with conditional deletion of TLR4 in Kupffer cells, hepatocytes or hepatic stellate cells (AIM 3). Downstream targets of TLR4 will be identified by microarray in whole liver and isolated cell populations, and the functional involvement of candidate genes such as IL-6, IL-1, TNF, LTα, LTß or IL-17 will be investigated in knockout mice. Results from this study are likely to establish an important contribution of LPS and TLR4 to an inflammatory and procarcinogenic gut-liver axis pathway in ALD, and may lead to the development of novel therapeutic treatment strategies targeting the gut microbiota, TLR4 or specific downstream mediators.

描述（由申请人提供）：肝细胞癌 (HCC) 是第五大常见癌症，每年导致全世界约 500,000 人死亡。在美国，肝癌的发病率在过去三十年里几乎翻了一番。尽管 HCV 和非酒精性脂肪肝病诱发的 HCC 有所增加，但酒精仍然被认为是 HCC 发生的主要危险因素。众所周知，(i) LPS 水平在酒精性肝病 (ALD) 的所有阶段均高度升高，并且 (ii) ALD 早期阶段的炎症和损伤主要由脂多糖 (LPS) 及其受体 TLR4 介导。最近，NF-kB、IL-1、IL-6 和淋巴毒素 α 和 β 等炎症通路已被确定为非酒精性肝癌发生的关键因素。我们假设炎症信号在酒精性肝癌发生中发挥重要作用，并且 LPS 和 TLR4 是 ALD 中炎症驱动的增殖和肝癌发生的关键促进者。我们假设 LPS 和 TLR4 代表炎症致癌信号级联的最上游调节因子，例如 NF-kB、JNK、IL-1、IL-6、IL-17、淋巴毒素 α 和 ß。该应用的长期目标是确定 LPS 和 TLR4 作为促进酒精性肝癌发生的炎症性肠肝轴的关键贡献者，并开发预防或治疗酒精性 HCC 的新概念。 TLR4 在酒精性肝癌发生中的作用将在 TLR4ko 和 wt 小鼠中进行测试，这些小鼠接受启动剂量的二乙基亚硝胺 (DEN) 和随后的含酒精饮食 (AIM 1)。肠道微生物群对酒精性肝癌的影响将通过接受 DEN 和含酒精饮食治疗的肠道灭菌和无菌小鼠进行评估 (AIM 2)。 LPS 和 TLR4 促进酒精性 HCC 的靶细胞和分子机制将在骨髓嵌合小鼠和库普弗细胞、肝细胞或肝星状细胞中条件性删除 TLR4 的小鼠 (AIM 3) 中确定。 TLR4 的下游靶标将通过全肝和分离细胞群中的微阵列进行鉴定，并且将在基因敲除小鼠中研究候选基因（例如 IL-6、IL-1、TNF、LTα、LTß 或 IL-17）的功能参与。这项研究的结果可能会确定 LPS 和 TLR4 对 ALD 中炎症和致癌肠肝轴通路的重要贡献，并可能导致针对肠道微生物群、TLR4 或特定下游介质的新型治疗策略的开发。