Nkx2-1抑制肺腺癌進展

　　轉移性肺癌發(fā)病率高、患者愈后差，但其進展和轉移機制目前仍未闡明。我們通過等位基因條件控制構建了具有高頻KRAS激活點突變及P53途徑失活的人肺腺癌小鼠模型（KrasLSL-G12D/+；p53flox/flox）。由慢病毒介導的模型小鼠肺上皮細胞Kras癌基因體細胞激活突變和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，這表明疾病的進展尚需進一步的基因改變。通過慢病毒整合位點鑒別，我們得以分辨轉移和非轉移瘤并明確可區(qū)分這兩種不同類型腫瘤的基因表達改變。種間研究已證明NK2相關的同源轉錄因子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)。對轉移和非轉移瘤分離細胞進行基因引入和敲除實驗證實，Nkx2-1基因控制腫瘤分化并限制其在活體內的轉移潛能。對Nkx2-1調節(jié)基因的探究，對不同發(fā)展階段腫瘤的分析以及功能互補實驗均指示Nkx2-1對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節(jié)因子即高遷移率族蛋白A2（Hmga2）實現(xiàn)的。部分人肺腺癌中NKX2-1位點的擴增提示了它的致癌功能，而我們的數(shù)據(jù)明確顯示Nkx2-1水平下調與腫瘤低分化、高種植能力及高轉移傾向相關�？梢�，Nkx2-1對同一類型腫瘤同時具有致癌和抑癌功能，證實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