Role of heat shock transcription factor HSF1 in tumoroginesis

热休克转录因子HSF1在肿瘤发生中的作用

基本信息

批准号：
8817986
负责人：
NAHID F MIVECHI
金额：
$ 30.61万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-07-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8817986
关键词：
Ablation Accounting Address Adipose tissue Albumins Alcohol consumption Alleles Attenuated Automobile Driving Biochemical Genetics Bioenergetics Cancer Model Carcinogens Cell Death Cell Proliferation Cells Cessation of life ChIP-seq Chronic Complication DNA Binding Data Development Diet Disease Embryo Enzymes Etiology Excision Fatty Liver Funding Generations Genes Genetic Gluconeogenesis Glucose Glutamine Growth HSF1 Heat shock proteins Hepatic Hepatocyte Homeostasis Human Inflammation Insulin Resistance Lactic acid Lead Liver Liver diseases Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Mitochondria Modeling Molecular Mus Mutation Neoplasm Metastasis Obesity Oncogenes Organ Pathogenesis Pathway interactions Patients Phenotype Physiological Premalignant Primary carcinoma of the liver cells Refractory Regulation Research Risk Role Staging Stem cells Testing Therapeutic Therapeutic Effect Tissues Trans-Activators Transcription Factor AP-2 Alpha Transplantation Tumor Cell Line Tumor Suppression Viral hepatitis cancer cell chemotherapy environmental stressor genetic manipulation genome-wide glucose metabolism heat shock transcription factor heat-shock factor 1 hepatocellular carcinoma cell line in vivo innovation lipid biosynthesis lipid metabolism liver inflammation liver injury liver metabolism mouse model mutant non-alcoholic fatty liver novel novel strategies prevent public health relevance receptor recombinase retransplantation small hairpin RNA stress protein sulfotransferase tool tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the most common liver malignancy and accounts for a large proportion of cancer deaths worldwide. The disease develops after a long latency period as a complication of chronic liver injury and inflammation, primarily induced by alcohol use, viral hepatitis, or nonalcoholic fatty liver disease. Obesity and metabolic syndrome also increase the risk of HCC development. The therapeutic options for HCC are limited, with potential curative treatment available for less than one third of patients, due to the fact that HCC is, in general, refractory to chemotherapy treatment and becomes clinically symptomatic and detectable only at a late stage. This underscores the urgent need for further research on the mechanisms driving hepatic injury and on the molecular pathways that are vital to HCC progression and metastasis. Heat shock factor 1 (Hsf1), a major transactivator of stress proteins that protect cells against environmental stressors, has been implicated in the pathogenesis of cancer, but specific mechanisms by which Hsf1 may support cancer development remain elusive. During the previous funding period we discovered that genetic inactivation of Hsf1 in mouse cancer models leads to remarkable inhibition of HCC development. We have found a novel pathogenic mechanism whereby Hsf1 activation promotes growth of pre-malignant hepatocytes and HCC development by stimulating lipogenesis and perpetuating chronic hepatic metabolic disease induced by the carcinogen. Thus, Hsf1 is a potential target for control of hepatic steatosis, insulin resistance, and HCC development. In this application, we will test the hypothesis that tissue-specific or total body inactivation of Hsf1 wil result in HCC growth retardation and prevent cancer development by inhibiting tumor-promoting metabolic reprogramming. In addition, our hypothesis predicts that Hsf1 inactivation from total or metabolically active organs (e.g., liver, adipose tissues) will prevent or attenuate liver cancer development caused by dietary obesity and metabolic syndrome by interfering with tumor-promoting metabolic pathways as well as inflammation. In Aim 1, development of liver tumors will be initiated by carcinogen, stable expression of oncogenes or by genetic manipulation of cultured embryonic liver progenitor cells followed by their re- transplantation into the livers of recipient mice. Extended analyses will address the clinically important question of whether systemic total body inactivation of Hsf1 can reverse HCC progression without eliciting adverse physiological consequences. In Aim 2, we will determine the metabolic profile (glucose, glutamine, lipid metabolism and mitochondrial activity) of hsf1-proficient and hsf1-deficient liver cancer cells using a 13C isotopomer approach. Extended analyses will identify possible metabolic changes in liver tumors developed in cancer mouse models. In addition, we will determine the effects of tissue-specific Hsf1 ablation on dietary obesity-induced liver cancer. Thus, we will use unique mouse models and biochemical and genetic approaches to test the potential of Hsf1 targeting in human HCC.

描述（由申请人提供）：肝细胞癌（HCC）是最常见的肝脏恶性肿瘤，占全球癌症死亡的很大一部分。该疾病在长期潜伏期后发展为慢性肝损伤和炎症的并发症，主要由饮酒、病毒性肝炎或非酒精性脂肪肝引起。肥胖和代谢综合征也会增加患肝癌的风险。 HCC 的治疗选择有限，只有不到三分之一的患者可以获得潜在的治愈性治疗，因为 HCC 通常对化疗治疗无效，并且只有在晚期才会出现临床症状并可检测到。这强调了迫切需要进一步研究肝损伤的驱动机制以及对 HCC 进展和转移至关重要的分子途径。热休克因子 1 (Hsf1) 是一种应激蛋白的主要反式激活因子，可保护细胞免受环境应激源的影响，它与癌症的发病机制有关，但 Hsf1 支持癌症发展的具体机制仍不清楚。在之前的资助期间，我们发现小鼠癌症模型中 Hsf1 的基因失活可显着抑制 HCC 的发展。我们发现了一种新的致病机制，Hsf1 激活通过刺激脂肪生成并使致癌物诱导的慢性肝脏代谢疾病永久化，从而促进癌前肝细胞的生长和 HCC 的发展。因此，Hsf1 是控制肝脂肪变性、胰岛素抵抗和 HCC 发展的潜在靶点。在这个在应用中，我们将测试这样的假设：Hsf1 的组织特异性或全身失活将导致 HCC 生长迟缓，并通过抑制肿瘤促进的代谢重编程来预防癌症发展。此外，我们的假设预测，总的或代谢活跃的器官（例如肝脏、脂肪组织）中的 Hsf1 失活将通过干扰肿瘤促进代谢途径以及炎症来预防或减轻由饮食肥胖和代谢综合征引起的肝癌的发展。在目标1中，致癌物、癌基因的稳定表达或通过对培养的胚胎肝祖细胞进行基因操作，然后将其重新移植到受体小鼠的肝脏中，将引发肝脏肿瘤的发展。扩展分析将解决 Hsf1 全身性失活是否可以逆转 HCC 进展而不引起不良生理后果的临床重要问题。在目标 2 中，我们将确定 hsf1 丰富和 hsf1 缺乏的肝脏的代谢特征（葡萄糖、谷氨酰胺、脂质代谢和线粒体活性）使用 13C 同位素异构体方法研究癌细胞。扩展分析将确定癌症小鼠模型中肝脏肿瘤可能发生的代谢变化。此外，我们将确定组织特异性 Hsf1 消融对饮食肥胖诱发的肝癌的影响。因此，我们将使用独特的小鼠模型以及生化和遗传学方法来测试 Hsf1 靶向在人类 HCC 中的潜力。