TOR signaling and autophagy in obesity-promoted liver tumorigenesis

肥胖促进的肝脏肿瘤发生中的 TOR 信号传导和自噬

• 批准号: 8471075
• 负责人: Michael Karin
• 金额: $ 33.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-22 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471075
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Ablation; Adverse effects; Affect; Autophagocytosis; Cell physiology; Cells; Chronic; Complex; Consumption; Deterioration; Development; Diet; Employee Strikes; Epidemic; Epidemiologic Studies; Etiology; Family; Fatty acid glycerol esters; Feedback; Gene Targeting; Genes; Genetic; Goals; Growth; Hepatocarcinogenesis; Hepatocyte; Human; Immune; Incidence; Inflammation; Inflammatory; Interleukin-6; Lead; Light; Link; Lipids; Liver; Liver diseases; Liver parenchyma; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic stress; Mitochondria; Modeling; Molecular; Monitor; Mus; Mutant Strains Mice; Nitrosamines; Obese Mice; Obesity; Oncogenic; Organ; Oxidative Stress; Pathogenesis; Pathway interactions; Phosphorylation; Play; Prevention strategy; Preventive; Primary carcinoma of the liver cells; Procedures; Protein Biosynthesis; Protein Kinase; Protein p53; Proteins; Raptors; Reactive Oxygen Species; Regulation; Risk; Role; STAT3 gene; Signal Transduction; Sirolimus; Steatohepatitis; TNF gene; TSC1 gene; Therapeutic; Transplantation; Tumor Promoters; Tumor Promotion; Tumor Suppressor Proteins; cancer risk; design; glucose metabolism; in vivo; inhibition of autophagy; inhibitor/antagonist; innovative technologies; lipid biosynthesis; lipid metabolism; liver function; liver inflammation; liver injury; mouse model; mutant; neoplastic; neoplastic cell; non-alcoholic fatty liver; novel; novel strategies; oxidation; prevent; research study; tool; transcription factor; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Our goal is to understand the molecular mechanisms through which obesity and excessive fat consumption increase the risk of cancer development. Epidemiological studies have shown that of all cancers, obesity has the most dramatic effect on the common form of liver cancer - hepatocellular carcinoma (HCC). In addition to its important metabolic functions, the liver is an immune organ that is severely impacted by obesity, resulting in non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), inflammatory conditions that greatly increase HCC risk. To genetically and molecularly investigate how obesity increases HCC risk, we established mouse models in which liver fat accumulation (hepatosteatosis) strongly enhances development of chemically-induced HCC; models that a recent review found to be highly relevant to the etiology and pathogenesis of human HCC. Using these models, we had demonstrated that obesity-induced liver inflammation plays a key role in HCC pathogenesis by activating the oncogenic transcription factor STAT3. However, hepatosteatosis also results in chronic activation of Target of Rapamycin (TOR) complex 1 (TORC1), thereby suppressing autophagy. We postulate that TORC1 activation and suppressed autophagy are additional mechanisms that contribute to the molecular pathogenesis of obesity-promoted HCC. To investigate this central hypothesis of the current proposal, four specific aims will be pursued: 1) Determine whether inhibition of TORC1 prevents obesity-promoted hepatocarcinogenesis; 2) Investigate the contribution of chronic TORC1 activation to DEN-induced hepatocarcinogenesis; 3) Identify effector pathways that mediate TORC1 effects on obesity-promoted hepatocarcinogenesis; and 4) Examine whether TORC1 feedback regulation by Sestrin has a role in obesity-promoted hepatocarcinogenesis. Whereas the first two aims will ask whether TORC1 activation is required and sufficient for obesity-promoted hepatocarcinogenesis, the third aim will explore the hypothesis that the most critical pathogenic function of chronic TORC1 activation is suppression of basal autophagy. The last aim will investigate the connection between tumor suppressor p53 and the regulation of TORC1 activity and autophagy, which depends on expression of Sestrins, a small family of p53-regulated proteins that activate AMPK. Studies will be performed mainly in vivo using both constitutive and inducible gene targeting as well as a novel approach for isolation and specific manipulation of pre-neoplastic HCC initiating cells. We will also develop new tools for uncoupling TORC1 from inhibition of autophagy. Collectively, the proposed experiments will shed new light on the pathogenic mechanisms that link hypernutrition and obesity to tumor development and progression via TORC1 and its ability to suppress basal autophagy. The proposed studies will also lead to new preventive and therapeutic strategies that will reduce the toll of obesity-promoted liver cancer as well as other cancers, such as pancreatic cancer, that are also strongly impacted by the obesity epidemic.

描述（由申请人提供）：我们的目标是了解肥胖和脂肪消耗过多增加癌症发展风险的分子机制。流行病学研究表明，在所有癌症中，肥胖症对肝癌的常见形式 - 肝细胞癌（HCC）具有最大的作用。除了其重要的代谢功能外，肝脏是一种免疫器官，受肥胖症严重影响，导致非酒精性脂肪肝病（NAFLD）和脂肪性肝炎（NASH），炎症疾病大大增加了HCC风险。为了在遗传和分子上研究肥胖如何增加HCC风险，我们建立了小鼠模型，其中肝脏脂肪积累（肝炎）强烈增强了化学诱导的HCC的发展。最近的综述发现与人类HCC的病因和发病机理高度相关的模型。使用这些模型，我们证明了肥胖诱导的肝脏炎症通过激活致癌转录因子Stat3在HCC发病机理中起关键作用。然而，肝造菌病还会导致雷帕霉素（TOR）复合物1（TORC1）的靶标长期激活，从而抑制自噬。我们假设TORC1激活和抑制自噬是有助于肥胖促进性HCC的分子发病机理的其他机制。为了研究当前提案的这一中心假设，将追求四个具体目标：1）确定抑制torc1是否阻止了肥胖促进的肝癌发生； 2）研究慢性Torc1激活对DEN诱导的肝癌发生的贡献； 3）确定介导Torc1对肥胖促进的肝癌发生的效应途径； 4）检查Sestrin的TORC1反馈调节是否在肥胖的肝癌发生中起作用。尽管前两个目标将询问是否需要TORC1激活，并且足以满足肥胖的肝癌发生，但第三个目标将探讨以下假设：慢性TORC1激活的最关键的病原功能是抑制基底自噬的抑制。最后一个目标将研究肿瘤抑制p53与TORC1活性和自噬的调控，这取决于Sestrins的表达，Sestrins是一种激活AMPK的p53调节的蛋白质。研究将主要使用本构和诱导基因靶向以及一种新颖的方法进行分离和特异性操纵性肿瘤前HCC启动细胞的新方法进行研究。我们还将开发新的工具，以从抑制自噬中解开TORC1。总的来说，提出的实验将为通过TORC1及其抑制基底自噬的能力与肿瘤发展和进展的致病机制提供新的启示。拟议的研究还将导致新的预防和治疗策略，从而减少肥胖促进的肝癌以及其他癌症（例如胰腺癌）的损失，这些癌症也受到肥胖症流行的强烈影响。