Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma.
Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma.
复制标题
DOI：
10.1016/j.molcel.2013.02.018
复制
发表时间：
2013-04-25
期刊：
影响因子：
16
通讯作者：
Jacks, Tyler
中科院分区：
文献类型：
--
作者：
Snyder, Eric L.;Watanabe, Hideo;Magendantz, Margaret;Hoersch, Sebastian;Chen, Tiffany A.;Wang, Diana G.;Crowley, Denise;Whittaker, Charles A.;Meyerson, Matthew;Kimura, Shioko;Jacks, Tyler
组织特异性分化程序在癌症演变过程中变得失调。转录因子Nkx 2 -1是肺分化的主要调节因子，在低分化肺腺癌中下调。在这里，我们使用条件小鼠遗传学，以确定肺上皮细胞的身份如何改变后，失去了他们的主细胞命运调节。Nkx 2 -1在正常和肿瘤性肺中的缺失不仅导致肺特性的丧失，而且还导致向胃谱系的转化。Nkx 2 -1可能通过将转录因子Foxa 1和Foxa 2募集到肺特异性基因座从而阻止它们结合胃肠道靶点来维持肺特性。nkx 2 -1阴性鼠肺肿瘤模拟表达胃标志物的粘液性人肺腺癌。胃肠道转录因子Hnf 4 α的缺失导致Nkx 2 -1阴性肿瘤中胚胎原基因Hmga 2的去抑制。这些观察结果表明，活性和潜伏分化程序的丧失是肿瘤达到原始的低分化状态所必需的。
Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to determine how the identity of lung epithelial cells changes upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also conversion to a gastric lineage. Nkx2-1 is likely to maintain pulmonary identity by recruiting transcription factors Foxa1 and Foxa2 to lung-specific loci thus preventing them from binding gastrointestinal targets. Nkx2-1-negative murine lung tumors mimic mucinous human lung adenocarcinomas, which express gastric markers. Loss of the gastrointestinal transcription factor Hnf4α leads to de-repression of the embryonal protoncogene Hmga2 in Nkx2-1-negative tumors. These observations suggest that loss of both active and latent differentiation programs is required for tumors to reach a primitive, poorly differentiated state.
登录
查看更多内容
影响因子：
4
作者：
Kaestner, Klaus H.
通讯作者：
Kaestner, Klaus H.
影响因子：
64.5
作者：
Hatziapostolou M;Polytarchou C;Aggelidou E;Drakaki A;Poultsides GA;Jaeger SA;Ogata H;Karin M;Struhl K;Hadzopoulou-Cladaras M;Iliopoulos D
通讯作者：
Iliopoulos D
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
50.5
作者：
Berghmans, T.;Paesmans, M.;Sculier, J. -P.
通讯作者：
Sculier, J. -P.
影响因子：
5.3
作者：
Cattin, Anne-Laure;Le Beyec, Johanne;Ribeiro, Agnes
通讯作者：
Ribeiro, Agnes