MEN1、K-Ras共同调控肺癌电离辐射效应的研究

Tomorgenesis and treatment is the progress with multiple genes and multiple stages. We found that menin expression was markedly reduced in certain human primary lung adenocarcinoma. Our early study have unraveled a novel feedback loop of Ras and tumor suppressor gene MEN1 in lung adenocarcinoma. We reveal a novel molecular basis controlling the development or progression of lung cancer that is governed by the interplay between K-Ras and menin, but the effection in radiation is unclear. The project intends to study the molecular radiation biology of lung cancer. We will use the lung cancer cell lines with different expression levels of MEN1 and K-Ras, and the animal models such as K-RasG12D；Men1f/fCreER etc to study. The methods we will use includes flow cytometry, real time qRT-PCR, IP , ChIP and other key technologies. These will help us to discuss the the function of MEN1 and K-Ras in lung cancer ionizing radiation and the inherent mechanism. And we hope the project will provide a new target for lung cancer radiosensitization.

肿瘤的发生与治疗是多基因参与、多阶段发展的过程。我们前期证明了MEN1基因抑制肺癌细胞表型的崭新生物学功能及其机制；同时发现抑癌基因MEN1与原癌基因K-Ras相互作用共同维持肺癌恶性表型，但在放射治疗中的作用尚不清楚。本项目拟从分子放射生物学入手，采用MEN1、K-Ras不同表达程度的肺癌细胞系及K-RasG12D；Men1f/fCreER等细胞、动物模型，利用流式细胞仪、real time qRT-PCR、IP、ChIP等关键技术，深入探讨MEN1、K-Ras在肺癌电离辐射中的作用及调控机制。有助于深入了解肺癌放射过程的多基因调控机制，对以MEN1、K-Ras通路为靶点的放射增敏研究提供理论基础和全新靶点。

Menin与大量涉及转录调节、基因组稳定性、细胞分裂增殖、细胞周期调控的相关蛋白相互作用,发挥着多种多样的生物学效应。在肺癌中参与了肺癌的发生发展过程，但在肺癌细胞电离辐射效应中的作用尚不清楚。本研究通过电离辐射诱导肺癌细胞辐射效应，探讨了menin在辐射效应中的作用及机制。我们的研究发现，电离辐射不影响menin表达，但能引起menin磷酸化的增加。同时，menin不影响肺癌细胞电离辐射诱导的细胞凋亡，但menin干扰后能解除电离辐射诱导的肺癌细胞S期阻滞，其机制是menin通过ATM，chk2，p21信号通路参与肺癌辐射周期调控。这为以menin为靶点的放射增敏研究提供理论基础和全新靶点。