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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. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β ( TGF-β) plays central roles in endothelial-mesenchymal transition (End MT) involved in development and pathogenesis. Although End MT and epithelial-mesenchymal transition are similar processes, roles of micro RNAs in End MT are largely unknown. Here, we report that constitutively active micro RNA-31 (miR-31) is a positive regulator of TGF-β-induced End MT. Although the expression is not induced by TGF-β, miR-31 is required for induction of mesenchymal genes including α- SMA, actin reorganization and MRTF-A activation during End MT. We identified VAV3, a regulator of actin remodeling and MRTF-A activity, as a miR-31 target. Global transcriptome analysis further showed that miR-31 positively regulates End MT-associated unique secretory phenotype (End MT- SP) characterized by induction of multiple inflammatory chemokines and cytokines including CCL17, CX3 CL1, CXCL16, IL-6 and Angptl2. As a mechanism for this phenomenon, TGF-β and miR-31 suppress Stk40, a negative regulator of NF-κB pathway. Interestingly, TGF-β induces alternative polyadenylation ( APA)-coupled miR-31-dependent Stk40 suppression without concomitant miR-31 induction, and APA-mediated exclusion of internal poly(A) sequence in Stk40 3′ UTR enhances target efficiency of Stk40. Finally, miR-31 functions as a molecular hub to integrate TGF-β and TNF-α signaling to enhance End MT. These data confirm that constitutively active micro RNAs, as well as inducible micro RNAs, serve as phenotypic modifiers interconnected with transcriptome dynamics during End MT. [ABSTRACT FROM AUTHOR]