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Nuclear Factor I/B is an Oncogene in Small Cell Lung Cancer

ABSTRACT: Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed only after it has metastasized to distant sites (Meuwissen and Berns 2005; Cooper and Spiro 2006). Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels (Forgacs et al. 2001; Pleasance et al. 2010). Using a genetically-engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung (Jonkers et al. 2001; Vooijs et al. 2002; Meuwissen et al. 2003; Sage et al. 2003), we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear Factor I/B (Nfib) in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation.

ORGANISM(S): Mus musculus

PROVIDER: GSE29533 | GEO | 2011/12/08

SECONDARY ACCESSION(S): PRJNA141491

REPOSITORIES: GEO

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Nuclear Factor I/B is an Oncogene in Small Cell Lung Cancer

Project description:Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed only after it has metastasized to distant sites (Meuwissen and Berns 2005; Cooper and Spiro 2006). Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels (Forgacs et al. 2001; Pleasance et al. 2010). Using a genetically-engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung (Jonkers et al. 2001; Vooijs et al. 2002; Meuwissen et al. 2003; Sage et al. 2003), we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear Factor I/B (Nfib) in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation. Gene expression analysis of two replicates each of two independent mSCLC cell lines (3583T3 and 3151T4) stably expressing Nfib, Mycl1 or both Nfib and Mycl1

2011-12-08 | E-GEOD-29533 | biostudies-arrayexpress

NFIB is a driver of SCLC initiation, progression and metastasis in mouse and marks metastatic disease in patients

Project description:Small Cell Lung Cancer (SCLC) is the most aggressive type of lung cancer with early metastatic dissemination and invariable development of resistant disease for which no effective treatment is available to date. Mouse models of SCLC based on inactivation of Rb1 and Trp53 developed earlier showed frequent amplifications of two transcription factor genes: Nfib and Mycl. Overexpression of Nfib but not Mycl in SCLC mouse results in an enhanced and altered metastatic profile, and appears to be associated with genomic instability. NFIB promotes tumor heterogeneity with the concomitant expansive growth of poorly differentiated, highly proliferative, and invasive tumor cell populations. Consistent with the mouse data, NFIB expression in high-grade human neuroendocrine carcinomas correlates with advanced stage III/IV disease warranting its further assessment as a potentially valuable progression marker in a clinical setting. Genomic DNA from mouse small cell lung tumor samples was analyzed by mate pair sequencing and low coverage sequencing. And RNA from Nfib overexpressing mouse small cell lung cancer cell lines was further analyzed for high quality RNA profiles using Illumina Hiseq2500. This series contains only RNA-seq data.

2016-07-29 | E-GEOD-82005 | biostudies-arrayexpress

The NFIB/CARM1 Axis is a Therapeutic Target for Small Cell Lung Cancer

Project description:We identified NFIB as a CARM1 substrate and showed that this transcription factor utilizes CARM1 as a coactivator. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Using a SCLC mouse model, we show that both CARM1 and the CARM1 methylation site on NFIB are critical for the rapid onset of SCLC. By performing the high-throughput sequecing analysis, we found that CARM1-null and NFIB-R388K mutant mouse SCLC tumors share the ability to regulate chromatin accessbility and have similar gene expression pattern.

2022-02-07 | GSE195843 | GEO

Large-scale gene expression profiling of hepatocellular adenomas

Project description:Hepatocellular adenomas (HCA) are rare benign tumors mainly developed in women after 2 years of oral contraceptive use (Rooks et al., 1979). HCA are also related to other risk factors (obesity, vascular diseases, androgen and alcohol intake) or to different genetic diseases (Mac Cune Albright syndrome, glycogen storage diseases type 1a and MODY3 diabetes caused by HNF1A germline mutation) (Calderaro et al., 2013; Nault et al., 2013a). Bleeding and malignant transformation to hepatocellular carcinoma (HCC) can occur as severe complications observed respectively in 30-50% and 5% of the cases. In the past 10 years, we identified 4 major molecular subgroups of HCA defined by (1) mutations inactivating HNF1A (H-HCA, 35% of the HCA) (Bacq et al., 2003; Bluteau et al., 2002; Jeannot et al., 2010), (2) activation of ß-catenin by mutations in exon 3 (bHCA, 15%) (Chen et al., 2002), (3) inflammatory phenotype with STAT3 activation (IHCA, 50%) (Bioulac-Sage et al., 2009; Zucman-Rossi et al., 2006), (4) a tumor subgroup of HCA with Sonic Hedgehog pathway activation due to recurrent focal deletions (shHCA) (Nault et al. ,in preparation) and (5) the remaining unclassified tumors (UHCA, 10%) (Bioulac-Sage et al., 2009). Among bHCA, half displayed both inflammatory and ß-catenin activated phenotypes (bIHCA). Inflammatory adenomas (IHCA) are caused by IL6ST somatic mutation activating gp130 in 60% of the cases (Rebouissou et al., 2009) whereas other IHCA are mutated for STAT3 itself (Pilati et al., 2011) or GNAS (Nault et al., 2012) but in the remaining 30% cases no mutation (NM) were identified yet. This molecular classification is currently accepted in clinical practice using either immunohistochemical markers (Bioulac-Sage et al., 2009; Bioulac-Sage et al., 2007) or in radiology at MRI (Laumonier et al., 2008) and it has dramatically improved the diagnosis and prognostic assessment of HCA. HCC derived from HCA malignant transformation (HCC on HCA, 5%)

2019-10-01 | GSE88839 | GEO

Role of oxylipins in pathogen defense of potato

Project description:Oxylipins play a role in the response of plants to pathogens both as antimicrobial compounds and as signaling molecules. In potato, pathogen infection leads to the stimulation of the 9-lipoxygenase pathway (Göbel et al. 2001; 2002; Stumpe et al. 2001). In order to analyze whether 9-LOX-derived oxylipins such as colnele(n)ic acid (products of the 9-divinyl ether synthase reaction) act as signaling molecules for the activation of defense responses, transgenic potato plants (Solanum tuberosum cv. Désirée) were generated which express an RNAi construct directed against the pathogen-induced 9-lipoxygenase (Göbel et al. 2003) or against the pathogen-induced 9-divinyl ether synthase (Stumpe et al. 2001). Highly reduced transcript levels correlate with low levels of 9-lipoxygenase-derived oxylipins (Göbel et al. 2003). Transgenic and wild type plants were grown as sterile plants on MS medium supplemented with agar in a phytochamber with 16 h of light [200 µE] at 22 °C. After transfer to soil, plants were kept in a phytochamber with 16 h of light [200 µE], 18 °C and 60 % humidity for four weeks. Lower leaves were infiltrated with a suspension of Pseudomonas syringae pv. maculicola at a concentration of 108 cfu/ml MgCl2 or, as a control, 10 mM MgCl2-solution. RNA was isolated both from the infiltrated leaves and the upper, non-treated leaves using the trizol method. Subsequently, RNA was digested with DNase and purified via Qiagen RNeasy Kit (Qiagen, Hilden, Germany) according to the manufacturer´s instructions. Keywords: Direct comparison

2007-09-01 | GSE8221 | GEO

Nfib promotes Metastasis through a Widespread Increase in Chromatin Accessibility [ATAC-seq]

Project description:We describe Nfib as an important regulator of chromatin accessibility in Small cell lung cancer (SCLC).

2016-05-10 | GSE81255 | GEO

NFIB is a driver of SCLC initiation, progression and metastasis in mouse and marks metastatic disease in patients

2016-07-29 | GSE82005 | GEO

Small-RNAs in L4 and young adult stages

Project description:Small endogenous C. elegans RNAs from L4 and young adult worms were prepared for sequencing using a protocol derived from Batista et al., (2008) and Lau et al. (2001). The small-RNA libraries were constructed using a method that does not require a 5’ monophosphate (called 5’ monophosphate-independent method, Ambros et al., 2003) to profile secondary siRNAs that have 5’ triphosphorylated G. All preprocessed small-RNA reads were mapped to genome (ce6), allowing no mismatches. After excluding miRNAs, 21U RNAs, rRNAs, and other structural ncRNAs, the remaining reads were classified as 22G RNAs, 26G RNAs, and other siRNAs, based on their length and 5′ terminal nucleotide.

2012-06-13 | GSE36394 | GEO

Comparison of the transcription profile of B. subtilis clpX strain with B. subtilis clpX spx strain, reporting on Spx activity

Project description:In B. subtilis the unusual transcription factor Spx controls the thiol stress response regulon (Nakano et al 2003 PNAS 100:13603; Rochat et a. 2012 NAR 40:9751). Under normal growth conditions Spx is constantly degraded by the AAA+ protease complex ClpXP (Nakano et al 2001 MolMi 42:383). Comparing a B. subtilis clpX strain, where Spx levels are high, with a B. subtilis clpX spx double mutant strain which lacks Spx, will report on Spx dependent transcriptional control. We prepared total RNA of exponentially grown B. subtilis clpX and of B. subtilis clpX spx cells.

2014-09-01 | GSE50102 | GEO

KLF4 Time Course

Project description:A stably transfected inducible system for KLF4 was established in RKO cells as previously described (Chen et al., 2001; Chen et al., 2003). This cell line, called EcR-RKO/KLF4, contains stably transfected receptors for the insect hormone, ecdysone (EcR), and a full-length mouse KLF4 cDNA driven by a promoter that responds to ecdysone and its analogue, ponasterone A. Cells were treated with 5 µM ponasterone A (PA), for various time durations. To control for the experiment, the vehicle, ethanol, was added for the same periods of time. Keywords: Time course

2005-08-13 | GSE3113 | GEO

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