Role of p53 and the p53-inducible Sestrin1 and 2 genes in hepatocarcinogenesis

p53 和 p53 诱导型 Sestrin1 和 2 基因在肝癌发生中的作用

• 批准号: 7513043
• 负责人: Andrei Vladimirovich Budanov
• 金额: $ 7.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7513043
• 关键词: Abnormal Cell; Acetylcysteine; Address; Antioxidants; Attenuated; Autophagocytosis; Cancer Etiology; Cause of Death; Cell Death; Cells; Cessation of life; DNA Damage; Development; Diagnosis; Diethylnitrosamine; Exposure to; Gene Family; Genes; Genotoxic Stress; Glycolysis; Hepatocarcinogenesis; Hepatocyte; Histology; Human; Incidence; Inflammation; Injury; Injury to Liver; Knockout Mice; Laboratories; Liver; Malignant Conversion; Malignant Neoplasms; Mediating; Membrane; Mentors; Metabolic; Metabolic Activation; Metabolism; Modeling; Monitor; Mouse Strains; Mus; Organelles; Oxidative Stress; Phase; Prevention; Primary carcinoma of the liver cells; Process; Production; Protein Biosynthesis; Reactive Oxygen Species; Regulation; Research Personnel; Risk Factors; Role; SDZ RAD; Signal Pathway; Signal Transduction; Staging; Stress; TP53 gene; Tamoxifen; Therapeutic Intervention; Time; Tumor Suppression; Tumor Suppressor Proteins; Type II Epithelial Receptor Cell; Viral; Work; acute stress; angiogenesis; biological adaptation to stress; carcinogenesis; cell growth; hepatotoxin; human FRAP1 protein; mTOR Inhibitor; mTOR inhibition; mutant; novel; prevent; programs; recombinase; response; response to injury; size; toxicant; tumor

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the most common human malignancies and the third cause of death from cancer worldwide. Exposure to different hepatotoxins causing liver injury and DNA damage is the major risk factor of HCC. This proposal is focused on the role of p53 and p53-inducible Sestrin1 (Sesn1) and Sestrin2 (Sesn2) genes in protection against hepatotoxin-induced liver injury and hepatocarcinogenesis. During the last, 8 years I identified and characterized a novel Sestrin gene family, where Sesn1/2 genes are p53-dependent stress responsive genes involved in regulation of reactive oxygen species, the protection against oxidative stress, and the suppression of mTOR signaling. The activation of Sesn1/2 genes can inhibit cell growth and induce autophagy. For a long time our lab has used a model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. DEN-treatment induces liver injury, oxidative stress, inflammation and DNA damage, which contributes [sic] to HCC formation in mice. Our lab has shown that the factors mitigating liver damage inhibit HCC development. DEN-exposure activates p53 and induces Sesn1/2 genes in liver. Surprisingly, p53-deficiency augments liver injury. Furthermore, DEN-treatment inhibits mTOR signaling, an important regulator of autophagy, in Sesn2-dependent manner. I hypothesize that p53 and Sesn1/2 genes can suppress HCC formation through activation of autophagy, mitigation of liver injury, and inhibition of oxidative stress. Additionally they can suppress HCC progression by inhibiting angiogenesis and metabolic switch toward glycolisis [sic]. To study the role of p53 and Sesn1/2 genes in DEN-induced stress response and hepatocarcinogenesis I will: 1) Evaluate the role of p53 and Sesn1 12 genes in DEN-induced stress response and HCC formation. Using mouse strains with deficiency p53 and Sesn1/2 in liver, I will characterize the role of these genes in DEN-induced autophagy, cell death, and compensatory proliferation as well as the signaling pathways involved in regulation of these processes. 2) Determine whether autophagy protects against liver damage and HCC formation. To adress [sic] this aim I will examine the autophagy-impared [sic] Beclin1 mice. 3) Examine the role of p53 and Sesn1/2 genes in suppression of different stages of HCC development, will use mice with tamoxifen-regulated expression of Cre-recombinase to delete p53 and Sesn1 genes in time-controlled manner. 4) Define if antioxidants and mTOR inhibitor can reverse the effect of p53 and Sesn1/2 deficiency on stress response and hepatocarcinogenesis. These finding regarding potential involvement [sic] of p53 and Sestrins in liver carcinogenesis can be used for diagnosis of human HCC. Also these results will provide the potential value of p53 and Sestrins as targets for therapeutic interventions.

描述（由申请人提供）： 肝细胞癌（HCC）是最常见的人类恶性肿瘤之一，也是全球癌症的第三个死亡原因。暴露于导致肝损伤和DNA损伤的不同肝毒素是HCC的主要危险因素。该建议的重点是p53和p53诱导的Sestrin1（SESN1）和Sestrin2（SESN2）基因在抗肝毒素诱导的肝损伤和肝癌发生中的作用。在过去的8年中，我确定并表征了一种新型的sestrin基因家族，其中SESN1/2基因是p53依赖性应激响应基因，涉及活性氧的调节，氧化应激的保护和MTOR信号的抑制。 SESN1/2基因的激活可以抑制细胞生长并诱导自噬。很长一段时间以来，我们的实验室一直使用二乙基硝基胺（DEN）诱导的肝癌发生模型。 DEN治疗诱导肝损伤，氧化应激，炎症和DNA损伤，这有助于小鼠的HCC形成。我们的实验室表明，减轻肝脏损伤的因素抑制了HCC的发展。 DEN曝光激活p53并诱导肝脏中的SESN1/2基因。令人惊讶的是，p53缺陷增加了肝损伤。此外，DEN处理以SESN2依赖性方式抑制MTOR信号传导，这是自噬的重要调节剂。我假设p53和SESN1/2基因可以通过激活自噬，减轻肝损伤和抑制氧化应激来抑制HCC的形成。此外，它们可以通过抑制血管生成和代谢切换到糖溶质[SIC]来抑制HCC的进展。为了研究p53和SESN1/2基因在DEN诱导的应激反应和肝癌发生中的作用：1）评估p53和SESN1 12基因在DEN诱导的应激反应和HCC形成中的作用。使用肝脏中缺乏p53和SESN1/2的小鼠菌株，我将表征这些基因在DEN诱导的自噬，细胞死亡和补偿性增殖中的作用，以及参与调节这些过程的信号传导途径。 2）确定自噬是否可以防止肝脏损伤和HCC形成。为了加深这个目标，我将检查自噬所制备的[sic] beclin1小鼠。 3）检查p53和SESN1/2基因在抑制HCC发育阶段的作用，将使用他莫昔芬调节的CRE聚集酶表达的小鼠以时间控制的方式删除p53和SESN1基因。 4）定义抗氧化剂和MTOR抑制剂是否可以扭转p53和SESN1/2缺乏对应激反应和肝癌发生的影响。这些关于p53和sestrins在肝癌发生的潜在参与[SIC]的发现可用于诊断人类HCC。这些结果还将提供p53和sestrins作为治疗干预措施的靶标的潜在值。