The role of Sirt2 in haptocarcinogenesis

 描述（由申请人提供）：总结本提案的中心焦点是了解NAD依赖性脱乙酰酶sirtuin-2（Sirt 2）在肝细胞癌（HCC）中的作用。HCC是美国增长最快的癌症。目前，HCC的致病机制尚不完全清楚。了解驱动或介导HCC发展的分子信号通路对于鉴定用于预防或治疗HCC的新治疗靶点是重要的。Sirt 2参与生物过程的各个方面，如衰老，代谢和癌症。靶向Sirt 2作为一种有前途的治疗策略的兴趣越来越大。因此， 了解Sirt 2的生理功能。Sirt 2通常被认为是肿瘤抑制因子。然而，最近的研究表明，Sirt 2蛋白在HCC中过表达，并与HCC的不良预后相关。因此，Sirt 2在HCC中的作用仍然存在争议。通过体内模型研究Sirt 2在肝癌发生中的作用，将为肝癌的分子机制提供新的认识。这些见解也将为靶向Sirt 2作为治疗策略提供分子基础。在这个项目中，我们将通过使用获得和丧失功能的策略，研究Sirt 2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，以确定如何过度表达Sirt 2影响肝癌发生。此外，我们将使用可诱导的肝细胞特异性Sirt 2敲除小鼠模型来进一步研究肝细胞中Sirt 2的缺失如何影响c-MET/β-连环蛋白驱动的HCC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.