The role of Sirt2 in haptocarcinogenesis

 描述(由申请人提供)：概述本提案的中心焦点是了解NAD依赖的脱乙酰基酶sirtuin-2(SIRT2)在肝细胞癌(HCC)中的作用。在美国，肝癌是增长最快的癌症。目前，肝细胞癌的发病机制尚不完全清楚。了解驱动或调节肝细胞癌发生的分子信号通路对于识别预防或治疗肝细胞癌的新的治疗靶点非常重要。SIRT2参与生物过程的各个方面，如衰老、新陈代谢和癌症。人们越来越有兴趣将SIRT2作为一种有前途的治疗策略。因此，重要的是 了解SIRT2的生理功能。SIRT2通常被认为是一种肿瘤抑制因子。然而，最近的研究表明，SIRT2蛋白在肝细胞癌中高表达，并与肝细胞癌的不良预后相关。因此，SIRT2在肝细胞癌中的作用仍然存在争议。通过体内模型研究SIRT2在肝癌发生中的作用，将对肝癌的分子机制有新的认识。这些见解也将为靶向SIRT2作为治疗策略提供分子基础。在这个项目中，我们将通过功能获得和功能丧失的策略，研究SIRT2在体内肝癌发生中的作用。我们已经建立了一个新的转座子载体来确定过表达SIRT2如何影响肝癌的发生。此外，我们将使用可诱导的肝细胞特异性SIRT2基因敲除小鼠模型来进一步研究肝细胞中SIRT2的缺失如何影响c-met/？catenin驱动的肝细胞癌的形成和进展。

 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.