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

项目摘要/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，发展最快的肝细胞癌病因学具有令人担忧的未来 投射。然而，肥胖和NASH如何促进NASH驱动的肝细胞癌的发展是病态的。 明确，阻碍了对本病的全面认识和有效发展 治疗学。虽然P53是一个定义明确的肿瘤抑制因子，但它参与了NASH和相关的 人们对肝细胞癌知之甚少。在NASH饮食小鼠模型中，P53蛋白最初稳定在早期 NASH分期，但在肿瘤发生之前丢失，而P53丢失足以促进 纳什。在人类患者中，肥胖者的NASH驱动的肝癌细胞表现出较低的频率 基因组TP53失活与瘦肉型相比，提出了P53功能受到 NASH在不需要基因组P53丢失的情况下促进进展为肝细胞癌。 初步数据表明，肥胖和NASH深刻地塑造了癌症的基因类型。这个 这项建议的目的是了解肥胖和NASH如何影响P53的活性，以及 对P53的选择性压力促使肝癌的发生。中心假设是NASH-1对P53的抑制。 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。这个 提出了以下具体目标来检验这一假说：1)剖析P53和P53的功能 衰老，并确定p53下游效应分子在抑制NASH驱动的肝癌中的作用；2)确定 胆固醇及降胆固醇药物他汀类药物在NASH向肝癌转化过程中对P53活性的影响 转变以阐明抑制P53的机制。这些研究将应用于饮食中的小鼠 NASH和肝细胞癌模型以及最先进的分子生物学和遗传学工具。 研究结果将发现一种潜在的关键机制，将肥胖和NASH与肝脏联系起来 恶性肿瘤，以及P53和NASH的新生物学。这一结果还将揭示新的治疗方法 对抗NASH驱动的肝细胞癌的可能性，例如改变降胆固醇药物的用途和/或 在P53网络中探索新的易处理的靶点。

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.