Project description:Although Thyroid transcription factor-1 (TTF-1, encoded by NKX2-1 gene) is highly expressed in small cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), difference in the functional roles of TTF-1 between SCLC and LADC remains to be elucidated. The aim of this study was to clarify the differences in the TTF-1 binding regions and functional roles in SCLC and LADC. Employing chromatin immunoprecipitation-sequencing (ChIP-seq) , here we compared the genome-wide TTF-1-binding profiles and the TTF-1-mediated transcriptional programs in a SCLC and a LADC cell lines. We also investigated ASCL1 binding regions in SCLC cells. To validate whether the changes in TTF-1 or ASCL1 binding to the genome indeed resulted in changes in target gene expression, we performed RNA-seq transcriptome analyses in H209 cells with TTF-1 or ASCL1 knockdown. Data were also obtained from H441 cells transfected with TTF-1 siRNAs.
Project description:Although Thyroid transcription factor-1 (TTF-1, encoded by NKX2-1 gene) is highly expressed in small cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), difference in the functional roles of TTF-1 between SCLC and LADC remains to be elucidated. The aim of this study was to clarify the differences in the TTF-1 binding regions and functional roles in SCLC and LADC. Employing chromatin immunoprecipitation-sequencing (ChIP-seq) , here we compared the genome-wide TTF-1-binding profiles and the TTF-1-mediated transcriptional programs in a SCLC and a LADC cell lines. We also investigated ASCL1 binding regions in SCLC cells.
Project description:Although Thyroid transcription factor-1 (TTF-1, encoded by NKX2-1 gene) is highly expressed in small cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), difference in the functional roles of TTF-1 between SCLC and LADC remains to be elucidated. The aim of this study was to clarify the differences in the TTF-1 binding regions and functional roles in SCLC and LADC. Employing chromatin immunoprecipitation-sequencing (ChIP-seq) , here we compared the genome-wide TTF-1-binding profiles and the TTF-1-mediated transcriptional programs in a SCLC and a LADC cell lines. We also investigated ASCL1 binding regions in SCLC cells.
Project description:To determine miRNAs regulated by TTF-1 in SCLC cell lines, miRNA array analyses were carried out in NCI-H209 cells following TTF-1 knockdown
Project description:To investigate genes possibly regulated by TTF-1 in small cell lung cancer cell lines, we compared gene expression profiles of NCI-H209 and Lu139 cell lines electroporated with control and TTF-1 siRNAs.
Project description:We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) which we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the three genes were determined and used to risk stratify a non-small cell lung cancer (NSCLC) clinical dataset consisting of ninety-one early stage tumors. Co-activation of the TTF-1 and NKX2-8 pathways identified a cluster of patients with poor survival, representing approximately 20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with co-activation of TTF-1 and NKX2-8 was validated in two other independent clinical datasets. Further, lung cancer cell lines showing co-activation of the TTF-1 and NKX2-8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. Since TTF-1 and NKX2-8 lack specific inhibitors at the current time, we explored an alternative therapeutic strategy. Using signatures of signaling pathway activation, we identified deregulation of specific oncogenic pathways (Ras and Myc) in the TTF-1/NKX2-8 co-activated cohort. In vitro experiments demonstrated the ability of a Ras pathway-specific therapy to inhibit tumor cell growth in TTF-1/NKX-2 activated cells, thus, suggesting that modulation of the Ras pathway is a rational strategy to targeted therapy in high risk NSCLC patients with co-activation of specific lung developmental pathways. Keywords: Transcription factor expression analysis
Project description:We evaluated the role of TTF-1/NKX2-1 on Smad3 and Smad4 binding in lung cancer cell lines. Smad3 binding sites in A549 cells and Smad3, Smad4, and TTF-1/NKX2-1 binding sites in H441 cells were determined by ChIP-seq.
Project description:We determined and analyzed the effect of TTF-1/NKX2-1 on Smad3/Smad4 binding sites by ChIP-sequencing. We used expression microarrays to evaluate the effect of TTF-1/NKX2-1 siRNA on TGF-beta-induced gene expressions.