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，占全世界癌症死亡的很大比例。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，主要是由酒精饮酒，病毒肝炎或非酒精性脂肪肝病引起的。肥胖和代谢综合征还增加了HCC发育的风险。 HCC的治疗选择受到限制，由于HCC通常是对化学疗法治疗难治性的事实，因此不到三分之一的患者可以接受治疗治疗，并且在临床上是症状性的，并且仅在后期才能检测到。这强调了迫切需要进一步研究驱动肝损伤的机制以及对HCC进展和转移至关重要的分子途径。热休克因子1（HSF1）是保护细胞免受环境压力源的应激蛋白的主要反式激活剂，与癌症的发病机理有关，但是HSF1可能支持癌症发育的特定机制仍然难以捉摸。在上一个资金期间，我们发现小鼠癌模型中HSF1的遗传失活导致对HCC发育的显着抑制。我们发现了一种新型的致病机制，通过刺激致癌物诱导的脂肪生成和永久性慢性肝代谢疾病，HSF1激活促进了肝细胞前肝细胞和HCC发育的生长。因此，HSF1是控制肝脂肪变性，胰岛素抵抗和HCC发育的潜在目标。在这个应用，我们将检验以下假设：HSF1 WIL组织特异性或总体失活导致HCC生长延迟，并通过抑制促进肿瘤的代谢重编码来防止癌症发展。此外，我们的假设预测，HSF1从总或代谢活性器官（例如肝脏，脂肪组织）灭活将通过干扰饮食肥胖和代谢综合征引起的肝癌发展或减轻肿瘤促进肿瘤的代谢途径以及炎症以及炎症。在AIM 1中，肝肿瘤的发育将由致癌物，癌基因的稳定表达或通过遗传操纵培养的胚胎肝脏祖细胞的遗传操纵，然后将其重新移植到受体小鼠的肝脏中。扩展分析将解决临床上重要的问题，即HSF1的系统性全身失活是否可以反向HCC的进展，而不会引起不良生理后果。在AIM 2中，我们将确定HSF1促进和HSF1缺陷肝脏的代谢谱（葡萄糖，谷氨酰胺，脂质代谢和线粒体活性）使用13C同位素方法的癌细胞。扩展分析将确定癌小鼠模型中发生的肝肿瘤的代谢变化。此外，我们将确定组织特异性HSF1消融对饮食肥胖引起的肝癌的影响。因此，我们将使用独特的小鼠模型以及生化和遗传方法来测试人类HCC中HSF1靶向的潜力。