Role of the SIRT7/NPM pathway in lung cancer progression

SIRT7/NPM 通路在肺癌进展中的作用

• 批准号: 493080688
• 负责人: Dr. Alessandro Ianni, Ph.D.
• 金额: --
• 依托单位: Josep Carreras Leukaemia Research Institute
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/493080688?language=en
• 关键词: Role; SIRT7; NPM; pathway; lung

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.

肺癌是恶性肿瘤导致的第二大死亡原因，约85%的确诊患者表现为组织学亚型，统称为非小细胞肺癌（NSCLC）。肺肿瘤具有很强的侵袭性，确诊患者的预后很差。因此，揭示肺肿瘤发生的分子机制对于开发新的治疗方法至关重要。SIRT7是哺乳动物sirtuins家族中研究最少的成员，sirtuins是一类组蛋白/蛋白去乙酰化酶，参与肿瘤发生的不同步骤。最近，我们发现SIRT7与核仁蛋白核磷蛋白（NPM）相互作用并使其去乙酰化，以促进NPM介导的基因毒性应激后肿瘤抑制因子p53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抑制了NPM的几种肿瘤抑制功能，最突出的是稳定肿瘤抑制因子ARF和NPM介导的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依赖性和非依赖性机制来表征SIRT7活性对肺肿瘤发生的影响。我们相信，拟议的项目将导致鉴定新的分子途径维持肺癌的进展，可以针对开发创新的抗癌药物。