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: 8187381
• 负责人: Michael Karin
• 金额: $ 35.26万
• 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/8187381
• 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; 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. PUBLIC HEALTH RELEVANCE: The obesity epidemic has precipitated a marked increase in the incidence of hepatocellular carcinoma (HCC) or liver cancer. The mechanisms by which obesity increases HCC risk are not fully known but their understanding is required for the design of effective therapeutic and preventive strategies. We will use recently developed mouse models and innovative technology for isolation of pre-neoplastic cells to fully understand how obesity promotes HCC development.

描述（由申请人提供）：我们的目标是了解肥胖和过量脂肪消耗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，肥胖对常见形式的肝癌-肝细胞癌（HCC）的影响最显着。除了其重要的代谢功能外，肝脏是一种受肥胖严重影响的免疫器官，导致非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH），这些炎症性疾病大大增加了HCC的风险。为了从遗传学和分子学上研究肥胖如何增加HCC风险，我们建立了小鼠模型，其中肝脏脂肪积聚（脂肪肝）强烈增强化学诱导的HCC的发展;最近的综述发现该模型与人类HCC的病因学和发病机制高度相关。使用这些模型，我们已经证明肥胖诱导的肝脏炎症通过激活致癌转录因子STAT 3在HCC发病机制中起关键作用。然而，脂肪肝也导致雷帕霉素靶蛋白复合物1（TOR 1）的慢性激活，从而抑制自噬。我们推测，TORC 1激活和抑制自噬是导致肥胖促进的HCC分子发病机制的额外机制。为了研究这个中心假设，我们将有四个具体的目标：1）确定抑制TORC 1是否能阻止肥胖促进的肝癌发生; 2）研究TORC 1的慢性激活对DEN诱导的肝癌发生的贡献; 3）确定介导TORC 1对肥胖促进的肝癌发生的效应通路;和4）检查Sestrin对TORC 1的反馈调节是否在肥胖促进的肝癌发生中起作用。前两个目标是询问TORC 1激活是否是肥胖促进的肝癌发生所必需的和足够的，第三个目标是探索慢性TORC 1激活的最关键致病功能是抑制基础自噬的假设。最后一个目标将研究肿瘤抑制因子p53与TORC 1活性调节和自噬之间的联系，这取决于Sestrins的表达，Sestrins是一个小家族的p53调节蛋白，激活AMPK。研究将主要在体内进行，使用组成型和诱导型基因靶向以及一种新的方法，用于分离和特异性操作癌前HCC起始细胞。我们还将开发新的工具，将TORC 1与自噬抑制解偶联。总的来说，拟议的实验将揭示通过TORC 1及其抑制基础自噬的能力将营养过剩和肥胖与肿瘤发展和进展联系起来的致病机制。拟议的研究还将导致新的预防和治疗策略，减少肥胖促进的肝癌以及其他癌症（如胰腺癌）的死亡率，这些癌症也受到肥胖流行的强烈影响。 公共卫生相关性：肥胖症的流行促使肝细胞癌（HCC）或肝癌的发病率显著增加。肥胖增加HCC风险的机制尚不完全清楚，但需要了解这些机制以设计有效的治疗和预防策略。我们将使用最近开发的小鼠模型和创新技术分离肿瘤前细胞，以充分了解肥胖如何促进HCC的发展。