Role of the SIRT7/NPM pathway in lung cancer progression

肺癌是恶性肿瘤的第二大死因，约85%的确诊患者表现出一种组织学亚型，统称为非小细胞肺癌(NSCLC)。肺癌侵袭性很强，确诊患者预后很差。因此，揭示肺肿瘤发生的分子机制对于开发新的治疗方法是必不可少的。SIRT7是哺乳动物sirtuins家族中研究最少的成员，sirtuins是一类参与肿瘤发生的不同步骤的组蛋白/蛋白脱乙酰酶。最近，我们发现SIRT7与核仁蛋白核仁蛋白核磷脂(NPM)相互作用并去乙酰化，以促进NPM介导的肿瘤抑制因子P53在基因毒性应激后的稳定。NPM在癌症进展中也起着关键作用。我们的初步数据表明，SIRT7抑制NPM的几种肿瘤抑制功能，最显著的是稳定肿瘤抑制因子ARF和NPM介导的对肺癌细胞中原癌基因c-Myc的抑制。在拟议的项目中，我们的目标是通过体外和体内NPM依赖和独立的机制来表征SIRT7活性在肺肿瘤发生中的影响。我们相信，这项拟议的项目将导致识别支持肺癌进展的新的分子途径，这些途径可能被用于开发创新的抗癌药物。

Lung cancer is the second cause of death due to malignancy and around 85% of the diagnosed patients display a histological subtype collectively known as non-small cell lung cancer (NSCLC). Lung tumors are very aggressive and the prognosis of diagnosed patients is very poor. Thus, unveiling the molecular mechanisms underlying lung tumorigenesis is imperative for development of novel therapeutical approaches. SIRT7 is the least investigated member of the family of mammalian sirtuins, a class of histone/protein deacetylases involved in different steps of tumorigenesis. Recently, we discovered that SIRT7 interacts with and deacetylates the nucleolar protein nucleophosmin (NPM) to promote NPM-mediated stabilization of the tumor suppressor p53 following genotoxic stress. NPM plays also critical roles in cancer progression. Our preliminary data demonstrate that SIRT7 represses several tumor suppressive functions of NPM, most prominently the stabilization of the tumor suppressor ARF and NPM-mediated inhibition of the proto-oncogene c-Myc in lung cancer cells. In the proposed project, we aim to characterize the impact of SIRT7 activities in lung tumorigenesis through NPM-dependent and –independent mechanisms both in vitro and in vivo. We believe that the proposed project will lead to identification of novel molecular pathways sustaining lung cancer progression that could be targeted for development of innovative anti-cancer drugs.