The role and regulation of p53 in obesity-induced liver cancer

p53在肥胖诱发肝癌中的作用及调控

• 批准号: 10320352
• 负责人: Changyu Zhu
• 金额: $ 6.98万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320352
• 关键词: Biology; Cholesterol; Chronic Disease; Communities; Complication; Data; Development; Diet; Disease; Disease Progression; Etiology; Event; Frequencies; Future; Genetic; Genomics; Genotype; Goals; Hepatocyte; Human; Impairment; Investigation; Kinetics; Knowledge; Link; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Molecular; Molecular Biology; Molecular Genetics; Mus; Neoplastic Cell Transformation; Obesity; Oncogenes; Output; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Premalignant Cell; Primary carcinoma of the liver cells; Process; Regulation; Repression; Risk; Risk Factors; Role; Shapes; Signal Transduction; TP53 gene; Testing; Therapeutic; Thinness; Transgenic Mice; Tumor Suppressor Proteins; base; cancer genetics; combat; dietary; global health; insight; liver development; mouse model; nonalcoholic steatohepatitis; novel; novel strategies; novel therapeutics; obese person; pressure; response; senescence; targeted treatment; therapeutic target; therapeutically effective; tool; transcriptomics; translational potential; tumor; tumorigenesis

Project Summary/Abstract Obesity is a prevalent global health problem, and it increases the overall risks of many types of chronic diseases and cancers. Nonalcoholic steatohepatitis (NASH) is a major liver complication of obesity, and importantly, the fastest growing etiology of hepatocellular carcinoma (HCC) with alarming future projections. However, how obesity and NASH contribute to the development of NASH-driven HCC is ill- defined, hindering the comprehensive understanding of the disease and the development of effective therapeutics. While p53 is a well-defined tumor suppressor, its involvement in NASH and associated HCC is poorly understood. In a dietary mouse model of NASH, p53 protein is initially stabilized in early stages of NASH but lost prior to tumorigenesis, while p53 loss is sufficient to promote HCC in mice with NASH. In human patients, NASH-driven HCCs from obese subjects display a lower frequency of genomic TP53 inactivation compared to lean ones, raising the idea that p53 functions are impaired by NASH that facilitates the progression to HCC without necessitating genomic p53 loss. The preliminary data suggest that obesity and NASH profoundly shape the cancer genotypes. The objective of this proposal is to understand how obesity and NASH influence the activity of p53, as well as the selective pressure against p53 to drive HCC. The central hypothesis is that p53 inhibition by NASH- associated cholesterol accumulation is an early and critical event linking NASH to tumorigenesis. The following specific aims are proposed to test the hypothesis: 1) to dissect the functions of p53 and senescence, and to identify p53 downstream effectors in suppressing NASH-driven HCC; 2) to determine the effects of cholesterol and cholesterol-lowering drug statin on p53 activity during NASH-to-HCC transition to elucidate a mechanism by which p53 is inhibited. These studies will apply a dietary mouse model of NASH and HCC along with the state-of-art tools of molecular biology and genetics. Findings from the studies will discover a potentially critical mechanism linking obesity and NASH to liver malignancy, as well as the novel biology of p53 and NASH. The results will also reveal new therapeutic possibilities to combat NASH-driven HCC, such as repurposing cholesterol-lowering drug and/or exploring new tractable targets within the p53 network.

项目总结/摘要 肥胖是一个普遍的全球健康问题，它增加了许多类型的慢性疾病的总体风险。 疾病和癌症。非酒精性脂肪性肝炎（NASH）是肥胖的主要肝脏并发症， 重要的是，肝细胞癌（HCC）的病因增长最快，前景令人担忧， 预测。然而，肥胖和NASH如何促进NASH驱动的HCC的发展是不好的。 定义，阻碍了对疾病的全面了解和有效的发展 治疗学虽然p53是一种明确的肿瘤抑制因子，但它参与NASH及其相关疾病 对HCC了解甚少。在NASH的饮食小鼠模型中，p53蛋白最初在早期稳定。 在NASH的小鼠中，p53的缺失足以促进HCC的发生，但在肿瘤发生之前p53的缺失足以促进HCC的发生。 纳什在人类患者中，来自肥胖受试者的NASH驱动的HCC显示出较低的肝硬化发生频率。 基因组TP 53失活相比，瘦的，提出了这样的想法，即p53功能受损， NASH促进HCC的进展，而不需要基因组p53丢失。 初步数据表明，肥胖和NASH深刻地塑造了癌症基因型。的 该提案的目的是了解肥胖和NASH如何影响p53的活性，以及 对p53的选择性压力驱动HCC。核心假设是NASH对p53的抑制作用- 相关的胆固醇积累是将NASH与肿瘤发生联系起来的早期和关键事件。的 本研究拟从以下几个方面对这一假说进行验证：1）研究p53的功能， 衰老，并鉴定抑制NASH驱动的HCC中的p53下游效应物; 2）确定 胆固醇和降胆固醇药物他汀类药物对NASH转HCC过程中p53活性的影响 转换以阐明p53被抑制的机制。这些研究将应用于饮食小鼠 沿着最先进的分子生物学和遗传学工具， 研究结果将发现肥胖和NASH与肝脏之间的潜在关键机制 恶性肿瘤，以及p53和NASH的新生物学。结果还将揭示新的治疗方法， 对抗NASH驱动的HCC的可能性，例如再利用降胆固醇药物和/或 在p53网络中探索新的易处理的靶点。