Nkx2-1抑制肺腺癌进展

　　转移性肺癌发病率高、患者愈后差，但其进展和转移机制目前仍未阐明。我们通过等位基因条件控制构建了具有高频KRAS激活点突变及P53途径失活的人肺腺癌小鼠模型（KrasLSL-G12D/+；p53flox/flox）。由慢病毒介导的模型小鼠肺上皮细胞Kras癌基因体细胞激活突变和P53缺失可致肺腺癌发生。虽然已知特定基因的变异可诱发肿瘤，但其中仅有部分可发生癌变，这表明疾病的进展尚需进一步的基因改变。通过慢病毒整合位点鉴别，我们得以分辨转移和非转移瘤并明确可区分这两种不同类型肿瘤的基因表达改变。种间研究已证明NK2相关的同源转录因子Nkx2-1（又称Ttf-1或Titf1）可能是肿瘤恶变的抑制因子。在此小鼠模型中，Nkx2-1阴性是肿瘤极低分化的特征性表现。对转移和非转移瘤分离细胞进行基因引入和敲除实验证实，Nkx2-1基因控制肿瘤分化并限制其在活体内的转移潜能。对Nkx2-1调节基因的探究，对不同发展阶段肿瘤的分析以及功能互补实验均指示Nkx2-1对肿瘤的抑制作用一定程度上是通过抑制胚胎源性的染色体限制调节因子即高迁移率族蛋白A2（Hmga2）实现的。部分人肺腺癌中NKX2-1位点的扩增提示了它的致癌功能，而我们的数据明确显示Nkx2-1水平下调与肿瘤低分化、高种植能力及高转移倾向相关。可见，Nkx2-1对同一类型肿瘤同时具有致癌和抑癌功能，证实它是一种双向功能家系因子。

　　Nature 473， 101–104 （05 May 2011） doi：10.1038/nature09881

　　原文

　　Suppression of lung adenocarcinoma progression by Nkx2-1

　　Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma， which frequently harbours activating point mutations in KRASand inactivation of the p53 pathway， using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+；p53flox/flox mice initiates lung adenocarcinoma development. Although tumours are initiated synchronously by defined genetic alterations， only a subset becomes malignant， indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 （also called Ttf-1