The role of Sirt2 in haptocarcinogenesis

Sirt2 在触癌发生中的作用

• 批准号: 9029308
• 负责人: Wei Qiu
• 金额: $ 7.55万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029308
• 关键词: Address; Affect; Age-Months; Aging; Biological Process; Cell Proliferation; Cells; Deacetylase; Development; Endothelial Cells; Goals; Health; Hepatocarcinogenesis; Hepatocyte; Human; Knockout Mice; Kupffer Cells; Liver; Liver diseases; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Molecular; Mouse Strains; Organ; Pathogenesis; Patients; Physiological; Play; Primary carcinoma of the liver cells; Proteins; Proto-Oncogene Proteins c-akt; Role; Sampling; Signal Pathway; Signal Transduction; Sleeping Beauty; Survival Rate; System; Testing; Therapeutic; Tumor Suppressor Proteins; United States; advanced disease; base; beta catenin; carcinogenesis; drug metabolism; effective therapy; epithelial to mesenchymal transition; hepatocellular carcinoma cell line; in vivo; in vivo Model; insight; interest; knock-down; loss of function; member; mouse model; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; prevent; stellate cell; tumor; tumor metabolism; tumorigenesis; tumorigenic; vector

 DESCRIPTION (provided by applicant): Summary The central focus of this proposal is to understand the role of the NAD-dependent deacetylase sirtuin-2 (Sirt2) in hepatocellular carcinoma (HCC). HCC is the most rapidly increasing cancer in the United States. Currently, the pathogenic mechanisms underlying HCC are not fully known. Understanding the molecular signaling pathways that drive or mediate the development of HCC is important for the identification of novel therapeutic targets for preventing or treating HCC. Sirt2 is involved in various aspects of biological processes, such as aging, metabolism and cancer. There is a growing interest in targeting Sirt2 as a promising therapeutic strategy. Therefore, it is important to comprehend the physiological functions of Sirt2. Sirt2 is generally believed to be a tumor suppressor. However, recent studies showed that Sirt2 protein is overexpressed in HCC and correlated with poor prognosis of HCC. Thus, the role of Sirt2 in HCC remains controversial. Studying the role of Sirt2 in hepatocarcinogenesis by in vivo models will reveal new insights into the molecular mechanisms of HCC. Such insights will also provide a molecular basis for targeting Sirt2 as a therapeutic strategy. In this project, by using gain- and loss-of-function strategies, we will study the role of Sirt2 in hepatocarcinogenesis in vivo. We have generated a new transposon vector to determine how overexpression Sirt2 affects hepatocarcinogenesis. In addition, we will use an inducible hepatocyte-specific Sirt2-knockout mouse model to further study how deletion of Sirt2 in hepatocytes affects c-MET/ß-catenin-driven HCC formation and progression.

 描述（由适用提供）：总结该提案的主要重点是了解NAD依赖性脱乙酰基酶Sirtuin-2（SIRT2）在肝细胞癌（HCC）中的作用。 HCC是美国最快增加的癌症。当前，HCC背后的致病机制尚不完全清楚。了解驱动或介导HCC发展或介导HCC发展的分子信号通路对于鉴定用于预防或治疗HCC的新型治疗靶标很重要。 SIRT2参与了生物过程的各个方面，例如衰老，代谢和癌症。将SIRT2作为一种有前途的治疗策略越来越兴趣。因此，这很重要 理解SIRT2的身体功能。通常认为SIRT2是肿瘤抑制剂。但是，最近的研究表明，SIRT2蛋白在HCC中过表达，并且与HCC的预后不良相关。这是SIRT2在HCC中的作用仍然存在争议。研究SIRT2在体内模型中的作用在肝癌发生中，将揭示对HCC分子机制的新见解。这种见解还将为将SIRT2作为治疗策略提供分子基础。在这个项目中，通过使用功能丧失策略，我们将研究SIRT2在体内肝癌发生中的作用。我们已经产生了一个新的转座子载体，以确定过表达SIRT2如何影响肝癌发生。此外，我们还将使用诱导的肝细胞特异性SIRT2-KNOCKOUT小鼠模型来进一步研究肝细胞中SIRT2的删除如何影响C-MET/ß-catenin驱动的HCC形成和进展。