Lung adenocarcinoma metastasis is suppressed by the alveolar lineage transcription factors GATA6 and HOPX.

Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype. mRNA profiles of human lung Adenocarcinoma PC9 cell lines infected with lentivirus harboring shRNA of control and shRNA of both GATA6 and HOPX were generated by deep sequencing, in triplicate, using Illumina HiSeq2000.

介导正常细胞分化的分子程序，在部分癌症的肿瘤发生及肿瘤细胞存活过程中发挥不可或缺的作用。目前学界对细胞谱系限制性基因如何特异性影响肿瘤转移的机制仍不甚明晰。在肺癌研究中，我们团队鉴定出一套优先与远端气道上皮分化及肺腺癌（lung adenocarcinoma, ADC）进展相关的转录程序。该程序的调控部分依赖于谱系特异性转录因子GATA6与HOPX；二者可通过协同调控重叠的肺泡分化与侵袭相关靶基因，限制性地削弱肺腺癌细胞的转移能力。综上，GATA6与HOPX是谱系选择性通路中的关键调控节点，该通路直接将气道上皮特化的效应因子与肺腺癌亚型的转移抑制过程建立起直接关联。本研究通过Illumina HiSeq2000平台完成深度测序，获取了感染携带对照短发卡RNA（short hairpin RNA, shRNA）以及同时靶向GATA6与HOPX的shRNA的人肺腺癌PC9细胞系的mRNA表达谱，实验设置三次生物学重复。