原纤毛是以微管为结构基础并突出于细胞表面的"天线状"细胞器，其结构和功能异常与肿瘤发生发展密切相关。文献报道，NEK蛋白激酶家族成员NEK-1和NEK-8参与调控原纤毛结构，但相关调控机制及NEK-1、NEK-8自身表达和活性调控机制均有待于进一步研究。本项目中，我们首次发现抑癌基因VHL缺失的肾癌细胞NEK-1和NEK-8表达水平较高，且我们已证实pVHL参与NEK-1和NEK-8的表达调控，并将探讨相关机制。鉴于VHL缺失细胞不能形成原纤毛结构，我们推测NEK-1、NEK-8参与介导pVHL维持原纤毛的结构稳定，并拟加以试验考证、阐明相关机制。本项目结果将有助于阐明NEK-1和NEK-8表达及活性调控的机制，完善pVHL维持肾癌细胞原纤毛结构稳定的机制研究，拓展NEK-1和NEK-8在肿瘤学领域的功能性研究。课题成果将有助于推进靶向NEK家族蛋白和调控原纤毛结构的抗肿瘤新药的研发。

The primary cilia is a microtubule-based antenna-like structure that emanates from the surface of cell. It is a sensory organelle that receives both mechanical and chemical signals from the environment, and serves as hub for the transduction of various signaling pathways including Hedgehog, PDGF and Wnt. Loss and dysfunction of primary cilia are related to occurrence and development of cancer. It is reported that NEK-1 and NEK-8 are involved in ciliary disassembly. However, the precise mechanism remains unelucidated. Moreover, the mechanisms underlying NEK-1 and NEK-8 regulation are poorly understood. In the present project, we found that the Von Hippel-Lindau tumor suppressor protein, also known as pVHL (the protein encoded by the VHL gene), deregulated the expression of NEK-1 and NEK-8, and we would like to investigate the inherent mechanism in the next step. Based on an overall consideration of pVHL deregulating the expression of NEK-1 and NEK-8, and cells deficient in pVHL can not form primary cilia, we supposed that pVHL maintained primary cilia stability by regulating the NEK-1 and NEK-8 in renal cell carcinoma cells. Our current study will help to shed a new light on understanding NEK-1 and NEK-8 regulation, and improve our understanding the role of pVHL in primary cilia control. The present project will promote exploring the possibilities of discovering new anti-cancer drugs by targeting NEK kinase family or primary cilia.