Examination of Apoptosis Signaling in Pancreatic Cancer by Computational Signal Transduction Analysis

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden,
PLoS ONE (Impact Factor: 3.23). 08/2010; 5(8):e12243. DOI: 10.1371/journal.pone.0012243
Source: PubMed


Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer death. Changes in apoptosis signaling in pancreatic cancer result in chemotherapy resistance and aggressive growth and metastasizing. The aim of this study was to characterize the apoptosis pathway in pancreatic cancer computationally by evaluation of experimental data from high-throughput technologies and public data bases. Therefore, gene expression analysis of microdissected pancreatic tumor tissue was implemented in a model of the apoptosis pathway obtained by computational protein interaction prediction.
Apoptosis pathway related genes were assembled from electronic databases. To assess expression of these genes we constructed a virtual subarray from a whole genome analysis from microdissected native tumor tissue. To obtain a model of the apoptosis pathway, interactions of members of the apoptosis pathway were analysed using public databases and computational prediction of protein interactions. Gene expression data were implemented in the apoptosis pathway model. 19 genes were found differentially expressed and 12 genes had an already known pathophysiological role in PDAC, such as Survivin/BIRC5, BNIP3 and TNF-R1. Furthermore we validated differential expression of IL1R2 and Livin/BIRC7 by RT-PCR and immunohistochemistry. Implementation of the gene expression data in the apoptosis pathway map suggested two higher level defects of the pathway at the level of cell death receptors and within the intrinsic signaling cascade consistent with references on apoptosis in PDAC. Protein interaction prediction further showed possible new interactions between the single pathway members, which demonstrate the complexity of the apoptosis pathway.
Our data shows that by computational evaluation of public accessible data an acceptable virtual image of the apoptosis pathway might be given. By this approach we could identify two higher level defects of the apoptosis pathway in PDAC. We could further for the first time identify IL1R2 as possible candidate gene in PDAC.

Download full-text


Available from: Christof Winter,
  • Source
    • "Using WikiPathways, authors can directly create a fully annotated pathway and either save it as an image to include in a publication or provide it as supplementary material. Several authors have already taken this approach (23,24), which offers additional advantages from the author's point of view. First, the pathway page at WikiPathways improves the reader experience, by providing links to additional detailed information and unambiguously annotated genes, proteins and metabolites. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we describe the development of WikiPathways (http://www.wikipathways.org), a public wiki for pathway curation, since it was first published in 2008. New features are discussed, as well as developments in the community of contributors. New features include a zoomable pathway viewer, support for pathway ontology annotations, the ability to mark pathways as private for a limited time and the availability of stable hyperlinks to pathways and the elements therein. WikiPathways content is freely available in a variety of formats such as the BioPAX standard, and the content is increasingly adopted by external databases and tools, including Wikipedia. A recent development is the use of WikiPathways as a staging ground for centrally curated databases such as Reactome. WikiPathways is seeing steady growth in the number of users, page views and edits for each pathway. To assess whether the community curation experiment can be considered successful, here we analyze the relation between use and contribution, which gives results in line with other wiki projects. The novel use of pathway pages as supplementary material to publications, as well as the addition of tailored content for research domains, is expected to stimulate growth further.
    Nucleic Acids Research 11/2011; 40(Database issue):D1301-7. DOI:10.1093/nar/gkr1074 · 9.11 Impact Factor
  • Source
    • "IPA analysis also highlighted the prevalence of genes related to cell death within the metastasis-signature. It comprised 42 protein-coding mRNAs related to apoptosis (19 down-regulated and 23 up-regulated), in line with the notion that perturbation of the normal programmed cell death is involved in the metastatic phenotype in pancreatic cancer [6,55]. Interestingly, we found 6 intronic lncRNAs mapped to locus of apoptosis-related genes among those present in the metastasis signature (ATF2, TGFβR2, MAP2K5, MAP3K1, DAPK1 and PTEN). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is known by its aggressiveness and lack of effective therapeutic options. Thus, improvement in current knowledge of molecular changes associated with pancreatic cancer is urgently needed to explore novel venues of diagnostics and treatment of this dismal disease. While there is mounting evidence that long noncoding RNAs (lncRNAs) transcribed from intronic and intergenic regions of the human genome may play different roles in the regulation of gene expression in normal and cancer cells, their expression pattern and biological relevance in pancreatic cancer is currently unknown. In the present work we investigated the relative abundance of a collection of lncRNAs in patients' pancreatic tissue samples aiming at identifying gene expression profiles correlated to pancreatic cancer and metastasis. Custom 3,355-element spotted cDNA microarray interrogating protein-coding genes and putative lncRNA were used to obtain expression profiles from 38 clinical samples of tumor and non-tumor pancreatic tissues. Bioinformatics analyses were performed to characterize structure and conservation of lncRNAs expressed in pancreatic tissues, as well as to identify expression signatures correlated to tissue histology. Strand-specific reverse transcription followed by PCR and qRT-PCR were employed to determine strandedness of lncRNAs and to validate microarray results, respectively. We show that subsets of intronic/intergenic lncRNAs are expressed across tumor and non-tumor pancreatic tissue samples. Enrichment of promoter-associated chromatin marks and over-representation of conserved DNA elements and stable secondary structure predictions suggest that these transcripts are generated from independent transcriptional units and that at least a fraction is under evolutionary selection, and thus potentially functional.Statistically significant expression signatures comprising protein-coding mRNAs and lncRNAs that correlate to PDAC or to pancreatic cancer metastasis were identified. Interestingly, loci harboring intronic lncRNAs differentially expressed in PDAC metastases were enriched in genes associated to the MAPK pathway. Orientation-specific RT-PCR documented that intronic transcripts are expressed in sense, antisense or both orientations relative to protein-coding mRNAs. Differential expression of a subset of intronic lncRNAs (PPP3CB, MAP3K14 and DAPK1 loci) in metastatic samples was confirmed by Real-Time PCR. Our findings reveal sets of intronic lncRNAs expressed in pancreatic tissues whose abundance is correlated to PDAC or metastasis, thus pointing to the potential relevance of this class of transcripts in biological processes related to malignant transformation and metastasis in pancreatic cancer.
    Molecular Cancer 11/2011; 10(1):141. DOI:10.1186/1476-4598-10-141 · 4.26 Impact Factor
  • Source
    • "There is evidence for a downregulated expression of the FAS receptor and translocation of the receptor to the cell surface is blocked by the overexpressed protein tyrosine phosphatase FAP-1. Additionally the strongly overexpressed decoy receptor DcR3 competes for the death ligand[16] [17] [18] [19] [20] [21] [22] [23] [24] [25]. The expression of the FAS ligand itself is upregulated[21] [26] [27]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is still a devastating malignancy with a 5 year survival of only 5%. Over the last 25 years treatment success has remained largely unchanged demonstrating the resistance of pancreatic cancer to conventional radiation and chemotherapy. Therefore, novel therapies target the molecular aberrations occurring in proliferation, metastasis, angiogenesis and especially apoptosis resistance. This review focuses on genetic alterations of the core signaling pathway of apoptosis and the influence for development of targeted therapies and multimodal treatment regimen. In pancreatic cancer the resistance to extrinsic apoptosis signals is caused by different competing factors. Decoy receptors are overexpressed and death signals can be redirected to non-apoptotic pathways by RIP1/TRAF2. Upon death receptor-mediated signaling DISC formation in pancreatic cancer cells is weak and the activation of the initiator caspase 8 is repressed by FAP 1 and c FLIP. Finally, additional activation of the mitochondrial pathway is required in these type II cells. At the intrinsic level an imbalance of the regulating Bcl 2 protein family has devastating effects. Silenced pro-apoptotic proteins fail to counteract the upregulated anti-apoptotic Bcl 2 members. Downstream the functionality of the effector caspase-activating apoptosome complex is disputable and furthermore the caspases are inhibited by overexpressed IAPs.
Show more