UNC5B/DAPK/p53 信号环路在肾癌细胞G2/M期阻滞中的作用及机制研究

Identification of effective signaling pathways and related molecular networks for repressing renal cancer cell proliferation has become an important frontier subject in the field of molecular oncology. Our recent work indicated the dependency receptor, UNC5B, as tumor suppressor gene in renal cancer. Our preliminary results further suggested that stable UNC5B expression activated DAPK and mediated renal cancer cells in the G2/M phase retardation via a p53/UNC5B/DAPK circuit. In this project, we aimed to further investigate the role of functional complex of UNC5B with DAPK in G2/M arrest through a series of molecular biology methods such as Co-Immunoprecipitation, gene silencing and DNA microarray. Furthermore, in vivo experiments from animals would be conducted to support the hypothesis that UNC5B/DAPK/p53 circuit may mediate the G2/M phase retardation, thereby inhibit the kidney cancer cell proliferation. The findings of this study may provide novel insights in demonstrating the direct relation of dependence receptors with cell cycle signaling, exploring multiple biological functions of dependence receptors, and effective solutions to malignant progression of renal cancer.

鉴定有效抑制肾癌细胞增殖的信号通路及相关分子网络已成为肿瘤分子治疗学领域的重要前沿课题.申请者最近的工作揭示了依赖性受体UNC5B在肾癌中的抑癌基因作用。我们的前期结果进一步提示稳定表达的UNC5B可能通过活化DAPK 所介导的p53/UNC5B/DAPK环路途径,介导肾癌细胞G2/M 期阻滞。本研究拟分别利用G2/M期同步化和UNC5B稳定过表达细胞模型，通过免疫沉淀、基因沉默及DNA微阵列等分子生物学方法，并结合体内动物实验结果，力图证明UNC5B/DAPK/p53 信号环路，介导了G2/M期阻滞，进而抑制了肾癌细胞增殖的假说。本研究不仅阐明了以UNC5B为代表的依赖性受体与细胞周期信号通路间的直接联系，为具有多重生物学功能的依赖性受体抑癌机制研究提供了新思路，也为解决抑制肾癌恶性进展的难题提供有效方案。

鉴定有效抑制肾癌细胞增殖的信号通路及相关分子网络已成为肿瘤分子治疗学领域的重要前沿课题.申请者最近的工作揭示了依赖性受体UNC5B在肾癌中的抑癌基因作用。我们的前期结果进一步提示稳定表达的UNC5B可能通过活化DAPK 所介导的p53/UNC5B/DAPK环路途径,介导肾癌细胞G2/M 期阻滞。本研究\分别利用G2/M期同步化和UNC5B稳定过表达细胞模型，通过免疫沉淀、基因沉默及DNA微阵列等分子生物学方法，并结合体内动物实验结果，证明了UNC5B/DAPK/p53 信号环路，介导了G2/M期阻滞，进而抑制了肾癌细胞增殖的假说。本课题组基于研究结果，在Bmc Cancer，International Journal Of Oncology， Journal Of Cellular And Molecular Medicine，Molecular Oncology，Cancer Gene Therapy，Onco Targets and Therapy，Biomedicine & Pharmacotherapy，中国继续医学教育等杂志发表相关SCI论文12篇，中文论文1篇，并在国内专业会议进行学术交流。本研究不仅阐明了以UNC5B为代表的依赖性受体与细胞周期信号通路间的直接联系，为具有多重生物学功能的依赖性受体抑癌机制研究提供了新思路，也为解决抑制肾癌恶性进展的难题提供有效方案。