Role of Nod2 and AMP-kinase in obesity-associated liver cancer

Nod2 和 AMP 激酶在肥胖相关肝癌中的作用

• 批准号: 10687174
• 负责人: Dipika Gupta
• 金额: $ 7.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687174
• 关键词: Address; Anthracenes; Autophagocytosis; Bacteria; Binding; Bioinformatics; Body Weight; Cancer Etiology; Carcinogens; Cell Line; Cell Proliferation; Cell physiology; Cessation of life; Chronic; Clinical; Crohn' s disease; Data; Development; Diabetes Mellitus; Disease; Future; Gene Expression; Genes; Goals; Health; Hepatocarcinogenesis; High Fat Diet; Hyperglycemia; Hyperlipidemia; Incidence; Individual; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Insulin Resistance; Liver; Liver neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Metformin; Methods; Mission; Mitochondria; Molecular; Monitor; Mus; Mutation; Natural Immunity; Obesity; Obesity associated liver disease; Pathway interactions; Pattern recognition receptor; Phosphotransferases; Predisposition; Prevention; Primary carcinoma of the liver cells; Principal Investigator; Process; Proteins; Public Health; Publishing; Regulation; Research; Risk Factors; Role; Role Concepts; STK11 gene; Testing; United States National Institutes of Health; adenylate kinase; biological adaptation to stress; cancer therapy; colitis associated cancer; diet-induced obesity; differential expression; dimethylbenzanthracene; experimental study; fatty liver disease; hepatocellular carcinoma cell line; in vivo; knock-down; lipid biosynthesis; liver cancer model; liver development; microbiota; mouse model; non-alcoholic fatty liver disease; obese person; obesity development; obesity prevention; obesity treatment; overexpression; programs; protein activation; pup; tumorigenesis; tumorigenic

Liver cancer is one of the fastest increasing causes of cancer-related deaths in the U.S. and worldwide. There are approximately 700,000 deaths worldwide each year due to liver cancer. Risk factors for liver cancer include nonalcoholic fatty liver disease, diabetes, and obesity, and the rising incidence in these diseases is paralleled with an increasing incidence in liver cancer. The development of hepatocellular carcinoma, the major subtype of liver cancer, is a multistep process and often starts with chronic inflammation. However, the molecular and cellular causes of inflammation remain poorly understood. Nod2 is a bacterial innate immunity protein and Nod2 deficiency is associated with inflammatory diseases, diet-induced obesity and metabolic dysfunction, and obesity-dependent liver cancer. Preliminary data, using a mouse model for hepatocellular carcinoma, predicts that the development of liver tumorigenesis in Nod2-deficient mice on high fat diet (HFD) is associated with an inhibition of the AMP- dependent kinase (AMPK) pathway. AMPK is a master regulator of metabolic reprogramming and cell proliferation. However, the role of the AMPK pathway in liver tumorigenesis in Nod2-deficient mice has not been demonstrated. In the current project, the hypothesis that there is decreased activation of the AMPK pathway in Nod2-/- tumorigenic mice, which contributes to the development of hepatic tumors in these mice will be tested. In Aim 1, the role of Nod2 in the activation of the AMPK pathway will be determined. WT and Nod2-/- mice will be treated with the carcinogen dimethylbenz[a]anthracene (DMBA) and maintained on HFD (DMBA+HFD) to induce liver tumors and regulation of proteins in the AMPK pathway will be determined in the liver. In Aim 2, the role of the AMPK pathway in the development of obesity-dependent hepatic tumors in Nod2-/- mice will be determined. Nod2-/- DMBA+HFD mice will be treated with metformin to activate AMPK and monitored for the development of hepatic tumors. The results from these experiments will provide proof-of-concept for the role of Nod2 in activation of the AMPK pathway and for the role of this pathway in protection from the development of hepatocellular carcinoma and will provide preliminary data for future in-depth studies to determine the molecular basis of obesity-dependent liver cancer.

肝癌是美国癌症相关死亡增长最快的原因之一 全世界。全球每年约有 70 万人死于肝癌。危险因素 肝癌的发病率包括非酒精性脂肪肝、糖尿病和肥胖，并且发病率不断上升 这些疾病与肝癌发病率的增加同时发生。肝细胞的发育 肝癌是肝癌的主要亚型，是一个多步骤的过程，通常始于慢性 炎。然而，炎症的分子和细胞原因仍然知之甚少。 Nod2 是一种细菌先天免疫蛋白，Nod2 缺乏与炎症有关 疾病、饮食引起的肥胖和代谢功能障碍以及肥胖依赖性肝癌。初步的 使用肝细胞癌小鼠模型的数据预测，肝脏的发育 食用高脂饮食 (HFD) 的 Nod2 缺陷小鼠的肿瘤发生与 AMP- 的抑制有关 依赖性激酶（AMPK）途径。 AMPK 是代谢重编程和细胞的主要调节因子 增殖。然而，AMPK 通路在 Nod2 缺陷小鼠肝脏肿瘤发生中的作用尚未明确。 已被证明。 在当前的项目中，假设 Nod2-/- 中 AMPK 通路的激活减少 将测试导致这些小鼠发生肝肿瘤的致瘤小鼠。瞄准 1，将确定Nod2在AMPK途径激活中的作用。 WT 和 Nod2-/- 小鼠将 用致癌物质二甲基苯并[a]蒽 (DMBA) 治疗并维持 HFD (DMBA+HFD) 诱发肝脏肿瘤，并在肝脏中确定 AMPK 通路中蛋白质的调节。在目标 2 中， AMPK 通路在 Nod2-/- 小鼠肥胖依赖性肝肿瘤发展中的作用将是 决定。 Nod2-/- DMBA+HFD 小鼠将用二甲双胍治疗以激活 AMPK 并监测 肝脏肿瘤的发展。这些实验的结果将为以下作用提供概念验证： Nod2 在 AMPK 通路的激活中以及该通路在防止 肝细胞癌，将为今后的深入研究提供初步数据，以确定 肥胖依赖性肝癌的分子基础。