Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA291647 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2140730.fastq.gz | Fastqsanger.gz | |||
| SRR2140731.fastq.gz | Fastqsanger.gz | |||
| SRR2140732.fastq.gz | Fastqsanger.gz | |||
| SRR2140733.fastq.gz | Fastqsanger.gz | |||
| SRR2140734.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
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Project description:Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastat ic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2- 1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently downregul ated in metastatic cells compared to non-metastatic cells. Knockdown of these three factors acts synergistically and is s ufficient to promote the metastatic potential of non-metastatic cells to that of naturally arising metastatic cells in vi vo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of th e genes expression differences between the non-metastatic and metastatic states in lung adenocarcinoma, including upregul ated expression of the invadopodia component Tks5long, the embryonal proto-oncogene Hmga2, and the epithelial-to-mesenchy mal mediator Snail. Finally, analyses of tumors from a genetically-engineered mouse model and patients show that low expr ession of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal t hat a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory n odes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program.
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Project description:The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To better understand how genomic alterations of NKX2-1 drive tumorigenesis, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma, and analyzed DNA binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation from NKX2-1-amplified human lung adenocarcinoma cell lines. Combining these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1, in addition to consensus binding motifs including a nuclear hormone receptor signature and a Forkhead box motif in NKX2-1-bound sequences. RNA interference analysis of NKX2-1-amplified cells compared to non-amplified cells demonstrated that LMO3 mediates cell proliferation downstream of NKX2-1; cistromic analysis that NKX2-1 may cooperate with FOXA1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transducer of lineage specific cell survival of NKX2-1-amplified lung adenocarcinomas. NKX2-1 ChIP-seq from three lung adenocarcinoma cell lines with amplification of NKX2-1
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Project description:The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To better understand how genomic alterations of NKX2-1 drive tumorigenesis, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma, and analyzed DNA binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation from NKX2-1-amplified human lung adenocarcinoma cell lines. Combining these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1, in addition to consensus binding motifs including a nuclear hormone receptor signature and a Forkhead box motif in NKX2-1-bound sequences. RNA interference analysis of NKX2-1-amplified cells compared to non-amplified cells demonstrated that LMO3 mediates cell proliferation downstream of NKX2-1; cistromic analysis that NKX2-1 may cooperate with FOXA1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transducer of lineage specific cell survival of NKX2-1-amplified lung adenocarcinomas. NCI-H2009 cells with stable expression of either pLKO-Tet-Op-shGFP (n=4) or pLKO-Tet-Op-shNKX2-1 (pooled population; n=3 and a clone; n=3) were treated with 50ng/ml of doxycyline for 48 hours. Total RNA was extracted, gene expression profiling was performed and differential gene expression between shGFP and shNKX2-1 was analyzed to determine the effects by suppression of NKX2-1 in NCI-H2009 cells.
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Project description:The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To better understand how genomic alterations of NKX2-1 drive tumorigenesis, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma, and analyzed DNA binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation from NKX2-1-amplified human lung adenocarcinoma cell lines. Combining these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1, in addition to consensus binding motifs including a nuclear hormone receptor signature and a Forkhead box motif in NKX2-1-bound sequences. RNA interference analysis of NKX2-1-amplified cells compared to non-amplified cells demonstrated that LMO3 mediates cell proliferation downstream of NKX2-1; cistromic analysis that NKX2-1 may cooperate with FOXA1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transducer of lineage specific cell survival of NKX2-1-amplified lung adenocarcinomas.
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