氡是引起人类肺癌的关键因素之一，其作用机制尚未完全阐明，目前仍是关注的焦点。核外线粒体在肿瘤发生发展中具有重要作用。我们前期的研究发现，在氡致肺上皮细胞恶性转化过程中大/小鼠肺组织线粒体拷贝数发生显著改变，并伴随着线粒体转录因子（TFAM）的表达增高。TFAM是调控细胞核基因和线粒体基因相互作用的关键转录因子，已证实NF-κB可调控转录TFAM。本项目拟在建立氡致人支气管上皮细胞恶性转化模型和BALB/c小鼠肺癌模型的基础上，探讨NF-κB对TFAM的转录调控，TFAM的表达以及TFAM对线粒体DNA（mtDNA）编码的呼吸链COXⅠ~Ⅲ和ND1~6的作用及其机制。从分子、细胞、动物多水平、多层次深入研究NF-κB/TFAM/mtDNA通路在氡致肺癌中的重要作用，从而为氡致肺癌的机制研究提供新的实验依据。

Lung cancer can be caused by radon, but its mechanism has not been completely elucidated. Mitochondria has an important role in tumor. In our previously study, we found that mtDNA copies and TFAM were increased with the accumulative dose of radon exposure. TFAM is a key transcription factor between regulating nuclear genes and mitochondrial genes. And NF- κB were confirmed to regulate TFAM. In the current project, we will investigate the potential role of NF- κB/TFAM/mtDNA in mouse lung cancer radon-induced. By using various methods including RT-PCR,Western-Blot as well as ChIP, we will first exam NF- κB/TFAM/mtDNA signal pathway level in mouse lung cancer and malignant transformation of human bronchial epithelial cells. And inhibitors were treated in human bronchial epithelial cells to test NF- κB/TFAM/mtDNA expression level. The results of this research hopefully provide a better supply of lung cancer induced by radon.

氡是空气中主要的天然放射性元素，是继烟草后引起人类肺癌的第二关键因素，被WHO（世界卫生组织）公布为19种主要环境致癌物之一，且被国际癌症研究机构列入室内主要致癌物。大量实验证实由于核外线粒体在肿瘤发生发展中具有重要作用；本项目中从线粒体角度探讨氡致肺癌的可能机制，采用小鼠和支气管上皮细胞建立氡染毒模型，检测发现在氡致肺上皮细胞恶性转化过程中小鼠肺组织线粒体拷贝数发生显著改变，并伴随着线粒体转录因子（TFAM）的表达增高。接下来我们通过大量实验证实TFAM是调控细胞核基因和线粒体基因相互作用的关键转录因子，上游NF-κB可调控转录TFAM。主要采用慢病毒转染、PCR以及CHIP和Westernblot等方法证实NF-κB对TFAM的转录调控；TFAM的表达以及TFAM对线粒体DNA（mtDNA）编码的呼吸链COXⅠⅢ和ND1~6的作用及其机制。根据以上研结果分析数据后我们阐释了NF-κB/TFAM/mtDNA通路激活在氡致肺癌中具有一定的作用，阐明线粒体损伤可能是其机制之一，为氡致肺癌的机制研究提供新的理论依据。