A Role for the Novel HAF-NFkappaB Axis in Driving Obesity-Associated Liver Cancer

新型 HAF-NFkappaB 轴在驱动肥胖相关肝癌中的作用

基本信息

批准号：
10676965
负责人：
Mei Yee Koh
金额：
$ 42.14万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676965
关键词：
Address Age Albumins Apoptosis Automobile Driving Cancer Etiology Carcinoma Cell Death Cell Death Induction Cells Cessation of life Complex Cytoprotection DNA Damage Disease Disease Progression Early Diagnosis Etiology Fatty Liver Female Fibrosis Functional disorder Genes Genetic Transcription Genomic Instability Goals HAF deficiency Hepatitis Hepatocyte Heterozygote Human Hypoxia Hypoxia Pathway In Vitro Incidence Infiltration Inflammatory Inflammatory Response Link Liver Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Measures Mediating Mediator Medical Metabolic Molecular Monitor Mus Neoplastic liver Nuclear Obesity Obesity Epidemic Outcome Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Phosphorylation Phosphotransferases Physiological Play Prevalence Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Prognostic Marker Proteins Role Sampling Severities Signal Transduction Small Interfering RNA Stress TNF gene TNFRSF5 gene Testing Time Tissues Transfection Transforming Growth Factor beta Tumor Necrosis Factor-Beta Tumor Suppressor Proteins Viral hepatitis cytokine diagnostic strategy dietary effective therapy fatty liver disease in vivo insight knock-down liver inflammation liver injury male metabolic-associated fatty liver disease mortality mouse model neoplastic new therapeutic target nonalcoholic steatohepatitis novel novel diagnostics novel therapeutic intervention overexpression p65 potential biomarker predictive marker prevent response screening therapeutic target therapy resistant treatment response treatment strategy ubiquitin-protein ligase

项目摘要

Hepatocellular carcinoma (HCC), the predominant primary cancer of the liver, is 4th leading cause of cancer deaths, and the fastest growing malignancy in the US. Advanced-stage HCC remains largely incurable due to a dismal response rate (<20%) and therapeutic resistance. The current obesity epidemic has been associated with the rising prevalence of metabolic (dysfunction) associated fatty liver disease (MAFLD) and its inflammatory component, non-alcoholic steatohepatitis (NASH), which can lead to HCC. MAFLD-HCC incidence is increasing dramatically, underscoring an unmet medical need for new diagnostic and treatment strategies. Here, we describe a novel tumor suppressor role of the Hypoxia-Associated Factor, HAF, in MAFLD-HCC. Both global haploinsufficiency and hepatocyte-specific deletion of HAF in mice result in HCC with hallmarks of NASH including severe steatosis with hepatocyte degeneration (hepatocyte ballooning), fibrosis, and increased inflammatory cell infiltration. HAF loss in both mouse models or by siRNA transfection in HCC cells is associated with decreased activation of the p65/p50 NF-κB transcriptional subunits, and in decreased levels of their upstream regulators, TAK1 and NEMO. Endogenous HAF forms a complex with NEMO and TAK1, suggesting that HAF modulates the NF-κB pathway by directly modulating the stability of these proteins, potentially through HAF’s E3 ubiquitin ligase activity. HAF knockdown was associated with increased spontaneous apoptosis, whereas HAF overexpression protected cells against TNF-induced cell death, suggesting that HAF may play a tumor suppressor role by protecting cells against death associated with liver inflammation (hepatitis) that can lead to HCC. Indeed, HAF levels are suppressed by conditions prevalent during hepatitis such as hypoxia and elevated TNF or TGF-β, whereas HAF are increased by DNA damage, suggesting that HAF may contribute to NF-κB activation in response to genomic instability in pre-neoplastic hepatocytes. Significantly, HAF was highly expressed in most cases of human hepatitis but was undetectable in 94% of human HCCs examined (65 cases). Thus, our hypothesis is that HAF plays a novel tumor suppressor role in HCC by facilitating NF-κB activation that promotes the survival of hepatocytes during hepatitis. Suppression of HAF by hypoxia or inflammatory cytokines during hepatitis results in increased cellular turnover that drives progression to NASH and HCC. Our overall goal is to identify new predictive/prognostic biomarkers or therapeutic targets for HCC, particularly those relevant to MAFLD-HCC. In Aim 1, we will test the hypothesis that HAF activates the NF-κB pathway by modulating the stability of TAK1 and NEMO, and thus identify the molecular mechanisms regulating the HAF- NF-κB axis. In Aim 2, we will test the hypothesis that HAF protects cells from excessive cell death during hepatitis, thus preventing progression to NASH and HCC. In Aim 3, we will test the hypothesis that HAF deregulation is associated with progression to HCC by investigating HAF expression in > 500 patient samples, to determine the association of HAF and its downstream targets to HCC initiation and progression or to treatment response.

肝癌（HCC）是肝的主要原发性癌症，是癌症的第四主要原因死亡和美国增长最快的恶性肿瘤。高级阶段HCC由于一个惨淡的反应率（<20％）和热电阻。当前的肥胖流行与代谢（功能障碍）相关脂肪肝疾病（MAFLD）及其炎症的患病率上升成分，非酒精性脂肪性肝炎（NASH），可能导致HCC。 MAFLD-HCC发病率正在增加在人口统计学上，强调了对新的诊断和治疗策略未满足的医疗需求。在这里，我们描述MAFLD-HCC中与缺氧相关因子HAF的新型肿瘤抑制作用。两者全球小鼠HAF的单倍不足和特定于肝细胞的缺失导致HCC具有NASH的标志包括肝细胞变性（肝细胞气球），纤维化和增加的严重脂肪变性炎症细胞浸润。小鼠模型中的HAF损失或HCC细胞中的siRNA转染与随着p65/p50 NF-κB转录亚基的激活改善，并以提高其水平上游监管机构TAK1和NEMO。内源性HAF与Nemo和Tak1形成了复合物，表明这可以通过直接调节这些蛋白质的稳定性来调节NF-κB途径 HAF的E3泛素连接酶活性。 HAF敲低与赞助凋亡增加有关而HAF过表达受保护的细胞免受TNF诱导的细胞死亡的影响，这表明HAF可能会发挥作用通过保护细胞免受与肝脏注射（肝炎）相关的死亡来抑制肿瘤作用的作用导致HCC。实际上，在肝炎（例如缺氧和 TNF或TGF-β升高，而HAF通过DNA损伤增加，这表明HAF可能有助于 NF-κB激活对肿瘤前肝细胞中基因组不稳定性的反应。值得注意的是，哈夫很高在大多数人类肝炎的情况下表达，但在检查的94％的人类HCC中无法检测到（65例）。这是我们的假设是，HAF通过支持NF-κB激活在HCC中起新颖的肿瘤抑制作用这促进了肝炎期间肝细胞的生存。缺氧或炎症抑制HAF 肝炎期间的细胞因子会导致细胞周转率增加，从而驱动纳什和HCC的发展。我们的总体目标是确定HCC的新的预测/预后生物标志物或治疗靶标，尤其是那些靶标与MAFLD-HCC有关。在AIM 1中，我们将测试HAF通过调节TAK1和NEMO的稳定性，从而确定调节HAF-的分子机制 NF-κB轴。在AIM 2中，我们将检验以下假设，即HAF保护细胞在肝炎期间免受过量细胞死亡，从而防止向NASH和HCC发展。在AIM 3中，我们将测试HAF放松管制的假设通过研究> 500个患者样本中的HAF表达，与向HCC的发展相关，以确定 HAF及其下游目标与HCC计划和进展或治疗反应的关联。