Unknown,Transcriptomics,Genomics,Proteomics

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NFATc1 integrates STAT3 inflammatory signals to promote Kras(G12D)-driven carcinogenesis in the pancreas.

ABSTRACT: Inflammatory transcription networks have been linked with the development of pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrate that NFATc1 is both necessary and sufficient to drive progression of KrasG12D-initiated PDAC, particularly in the context of inflammation. Significantly, nuclear NFATc1 accelerates PDAC development in KrasG12D mice, whereas conditional NFATc1 deletion or pharmacological inhibition attenuates inflammation-mediated carcinogenesis. Mechanistically, NFATc1 induces STAT3 expression, complex formation and signal integration in PDAC. Genome-wide ChIP-sequencing and expression analysis in cells derived from c.n.NFATc1;KrasG12D mice identified combinatorial NFATc1/STAT3 binding at chromatin enhancer sites and subsequent regulation of key molecules involved in oncogenic signaling, growth and inflammation. Together, this study supports the relevance of inflammatory transcription factor networks in pancreatic carcinogenesis and provides a theoretical platform for therapeutic targeting of NFATc1 nucleoprotein complexes in PDAC. NFATc1 ChIP followed by high throughput sequencing in primary murine pancreatic cancer cells (referred to as NKC cells) derived from transgenic mice with pancreas-specific constitutive activation of NFATc1 and KrasG12D mutation in the presence or absence of STAT3 shRNA; 2 ChIP samples (scramble DNA and shSTAT3 DNA) and 1 unenriched input control from the same chromatin pool.

ORGANISM(S): Mus musculus

SUBMITTER: Marek Bartkuhn

PROVIDER: E-GEOD-39969 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Epigenetic modifications, particularly DNA methylation have been increasingly implicated in cancer. Although some genes display aberrant methylation in pancreatic cancer, a comprehensive global analysis is yet to be performed. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), the methylation profile of 156 PDAC and 23 non-malignant pancreas was captured using high-density arrays. More than 90,000 CpG sites were significantly differentially methylated (DM) in PDAC relative to non-malignant pancreas, with pronounced alterations in a sub-set of 13,517 CpG sites. This sub-set of differentially methylated CpG sites segregated PDAC from non-malignant pancreas, regardless of tumour cellularity. As expected, PDAC hyper-methylation was most prevalent in the 5’ region of genes (including the proximal promoter, 5’UTR and CpG islands). From 3981 genes aberrantly methylated, approximately 36% showed significant correlation between methylation and mRNA expression levels. Pathway analysis revealed an enrichment of aberrant methylation in genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, Integrin signaling, Cell adhesion, Stellate cell activation and Axon guidance. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, SRGAP1, and MET suggested epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET expression. Hypo-methylation of MET and ITGA2 correlated with high gene expression, which correlated with poor survival of PDAC patients. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting known core signaling pathways with important implications for disease pathophysiology and therapy. This dataset includes gene expression data from 103 primary tumour samples. 86 samples from this dataset have already been deposited into GEO (GSE36924), and has been duplicated here since the data has been processed differently. This data is also available through the International Cancer Genome Consortium (ICGC) Data Portal (http://dcc/icgc.org), under the project code: Pancreatic Cancer (QCMG, AU). Access to the restricted clinical data must be made through the ICGC Data Access Compliance Office (http://www.icgc.org/daco). This dataset contains gene expression array data from 103 primary pancreatic ductal adenocarcinoma samples. All samples have 1 biological replicate. These data have corresponding methylation 450K array data (GSE49149).

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NFATc1 integrates STAT3 inflammatory signals to promote Kras(G12D)-driven carcinogenesis in the pancreas.

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