title: Advanced computational biology methods identify molecular switches for malignancy in an EGF mouse model of liver cancer.
abstract: The molecular causes by which the epidermal growth factor receptor tyrosine kinase induces malignant transformation are largely unknown. To better understand EGFs' transforming capacity whole genome scans were applied to a transgenic mouse model of liver cancer and subjected to advanced methods of computational analysis to construct de novo gene regulatory networks based on a combination of sequence analysis and entrained graph-topological algorithms. Here we identified transcription factors, processes, key nodes and molecules to connect as yet unknown interacting partners at the level of protein-DNA interaction. Many of those could be confirmed by electromobility band shift assay at recognition sites of gene specific promoters and by western blotting of nuclear proteins. A novel cellular regulatory circuitry could therefore be proposed that connects cell cycle regulated genes with components of the EGF signaling pathway. Promoter analysis of differentially expressed genes suggested the majority of regulated transcription factors to display specificity to either the pre-tumor or the tumor state. Subsequent search for signal transduction key nodes upstream of the identified transcription factors and their targets suggested the insulin-like growth factor pathway to render the tumor cells independent of EGF receptor activity. Notably, expression of IGF2 in addition to many components of this pathway was highly upregulated in tumors. Together, we propose a switch in autocrine signaling to foster tumor growth that was initially triggered by EGF and demonstrate the knowledge gain form promoter analysis combined with upstream key node identification.
authors.affiliation: BIOBASE GmbH, Wolfenbuettel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Stegmaier
authors.forename: Nico
authors.initials: N
authors.lastname: Voss
authors.forename: Tatiana
authors.initials: T
authors.lastname: Meier
authors.forename: Alexander
authors.initials: A
authors.lastname: Kel
authors.forename: Edgar
authors.initials: E
authors.lastname: Wingender
authors.forename: Juergen
authors.initials: J
authors.lastname: Borlak
mesh_terms: D000818:Animals; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D004273:DNA, Neoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004815:Epidermal Growth Factor / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D014157:Transcription Factors; D004815:Epidermal Growth Factor