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Advanced Computational Biology Methods Identify Molecular Switches for Malignancy in an EGF Mouse Model of Liver Cancer

机译：先进的计算生物学方法可识别EGF小鼠肝癌模型中恶性肿瘤的分子开关。

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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.
机译：表皮生长因子受体酪氨酸激酶诱导恶性转化的分子原因尚不清楚。为了更好地了解EGF的转化能力，将全基因组扫描应用于肝癌的转基因小鼠模型中，并进行了先进的计算分析方法，以结合序列分析和夹带图拓扑算法构建从头基因调控网络。在这里，我们确定了转录因子，过程，关键节点和分子，它们在蛋白质-DNA相互作用水平上仍是未知的相互作用伴侣。其中许多可以通过在基因特异性启动子识别位点的电动迁移带移分析和核蛋白的蛋白质印迹来证实。因此，可以提出一种新颖的细胞调节电路，该电路将细胞周期调节基因与EGF信号通路的成分相连接。对差异表达基因的启动子分析表明，大多数受调节的转录因子对肿瘤前或肿瘤状态均表现出特异性。随后对已鉴定的转录因子及其靶标上游的信号转导关键节点的搜索表明，胰岛素样生长因子途径使肿瘤细胞独立于EGF受体活性。值得注意的是，除此途径的许多成分外，IGF2的表达在肿瘤中也高度上调。我们共同提出了一种在自分泌信号传导方面的开关，以促进最初由EGF触发的肿瘤生长，并展示了通过启动子分析与上游关键节点识别相结合的知识获取。

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