Nkx2-1抑制肺腺癌進(jìn)展

　　轉(zhuǎn)移性肺癌發(fā)病率高、患者愈后差，但其進(jìn)展和轉(zhuǎn)移機(jī)制目前仍未闡明。我們通過等位基因條件控制構(gòu)建了具有高頻KRAS激活點(diǎn)突變及P53途徑失活的人肺腺癌小鼠模型（KrasLSL-G12D/+；p53flox/flox）。由慢病毒介導(dǎo)的模型小鼠肺上皮細(xì)胞Kras癌基因體細(xì)胞激活突變和P53缺失可致肺腺癌發(fā)生。雖然已知特定基因的變異可誘發(fā)腫瘤，但其中僅有部分可發(fā)生癌變，這表明疾病的進(jìn)展尚需進(jìn)一步的基因改變。通過慢病毒整合位點(diǎn)鑒別，我們得以分辨轉(zhuǎn)移和非轉(zhuǎn)移瘤并明確可區(qū)分這兩種不同類型腫瘤的基因表達(dá)改變。種間研究已證明NK2相關(guān)的同源轉(zhuǎn)錄因子Nkx2-1（又稱Ttf-1或Titf1）可能是腫瘤惡變的抑制因子。在此小鼠模型中，Nkx2-1陰性是腫瘤極低分化的特征性表現(xiàn)。對(duì)轉(zhuǎn)移和非轉(zhuǎn)移瘤分離細(xì)胞進(jìn)行基因引入和敲除實(shí)驗(yàn)證實(shí)，Nkx2-1基因控制腫瘤分化并限制其在活體內(nèi)的轉(zhuǎn)移潛能。對(duì)Nkx2-1調(diào)節(jié)基因的探究，對(duì)不同發(fā)展階段腫瘤的分析以及功能互補(bǔ)實(shí)驗(yàn)均指示Nkx2-1對(duì)腫瘤的抑制作用一定程度上是通過抑制胚胎源性的染色體限制調(diào)節(jié)因子即高遷移率族蛋白A2（Hmga2）實(shí)現(xiàn)的。部分人肺腺癌中NKX2-1位點(diǎn)的擴(kuò)增提示了它的致癌功能，而我們的數(shù)據(jù)明確顯示Nkx2-1水平下調(diào)與腫瘤低分化、高種植能力及高轉(zhuǎn)移傾向相關(guān)�？梢�，Nkx2-1對(duì)同一類型腫瘤同時(shí)具有致癌和抑癌功能，證實(shí)它是一種雙向功能家系因子。

　　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