Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is highly expressed in small-cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), but how its functional roles differ between SCLC and LADC remains to be elucidated. Here, we compared the genome-wide distributions of TTF-1 binding regions and the transcriptional programs regulated by TTF-1 between NCI-H209 (H209), a human SCLC cell line, and NCI-H441 (H441), a human LADC cell line, using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq). TTF-1 binding regions in H209 and H441 cells differed by 75.0% and E-box motifs were highly enriched exclusively in the TTF-1 binding regions of H209 cells. Transcriptome profiling revealed that TTF-1 is involved in neuroendocrine differentiation in H209 cells. We report that TTF-1 and achaete-scute homolog 1 (ASCL1, also known as ASH1, an E-box binding basic helix-loop-helix transcription factor, and a lineage-survival oncogene of SCLC) are coexpressed and bound to adjacent sites on target genes expressed in SCLC, and cooperatively regulate transcription. Furthermore, TTF-1 regulated expression of the Bcl-2 gene family and showed antiapoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and antiapoptotic gene expression by partly coordinating with ASCL1.

中文翻译：

---

小细胞肺癌和非小细胞肺癌中TTF-1结合DNA区域的比较分析。

甲状腺转录因子-1（TTF-1，由NKX2-1基因编码）在小细胞肺癌（SCLC）和肺腺癌（LADC）中高表达，但在SCLC和LADC之间其功能作用如何区别尚待观察阐明。在这里，我们比较了人SCLC细胞系NCI-H209（H209）和人LADC细胞NCI-H441（H441）之间TTF-1结合区的全基因组分布和TTF-1调控的转录程序使用染色质免疫沉淀测序（ChIP-seq）和RNA测序（RNA-seq）。H209和H441细胞中的TTF-1结合区相差75.0％，E盒基序仅高度富集于H209细胞的TTF-1结合区中。转录组分析显示，TTF-1参与H209细胞的神经内分泌分化。我们报告说，TTF-1和achaete-scute同源物1（ASCL1，也称为ASH1，E-box结合基本螺旋-环-螺旋转录因子，以及SCLC的谱系生存癌基因）共表达并与邻近位点结合在SCLC中表达的靶基因上，并协同调节转录。此外，TTF-1调节Bcl-2基因家族的表达，并在SCLC中显示抗凋亡功能。我们的发现表明，TTF-1通过与ASCL1的部分协调，促进SCLC的生长并促进神经内分泌和抗凋亡基因的表达。TTF-1调节Bcl-2基因家族的表达，并在SCLC中显示抗凋亡功能。我们的发现表明，TTF-1通过与ASCL1的部分协调，促进SCLC的生长并促进神经内分泌和抗凋亡基因的表达。TTF-1调节Bcl-2基因家族的表达，并在SCLC中显示抗凋亡功能。我们的发现表明，TTF-1通过与ASCL1的部分协调，促进SCLC的生长并促进神经内分泌和抗凋亡基因的表达。