Nax proteins and -sensitive responses only appeared when exogenous Nax was expressed

a larger impact than downstream genes, pathway-topology-based approaches, such as signaling-pathway impact analysis and ScorePAGE, qualify as third-generation methods. In particular, SPIA combines classical enrichment analysis and the perturbation on a given pathway, which allows it to capture the influence of A-83-01 upstream genes. Following SPIA, Vaske et al. proposed a method named PARADIGM, which integrates diverse high-throughput genomics information with known signaling pathways to provide patient-specific genomic inferences on the state of gene activities, complexes, and cellular processes. Recently, researchers proposed that key subpathway regions may represent the corresponding pathway and be more relevant for interpreting the associated biological phenomena. Moreover, several studies show that abnormalities in subpathway regions of metabolic pathways may contribute to the etiology of diseases. Subpathway analysis in signaling pathways has also been studied, resulting in approaches such as DEgraph, the clipper approach, and Pathiways. These are qualified as fourth-generation methods. In the present work, we combine the approaches of subpathway analysis and SPIA, which we call sub-SPIA, to identify biologically meaningful signaling pathways. One key problem in subpathway analysis is how to define a subpathway. Li et al. used the k-clique concept to define a subpathway. However, pathways are usually sparsely connected and are composed of many linear structures. The k-clique concept has two limitations: the relationship between DEGs in a subpathway may not exactly form a k-clique structure, and the k-clique algorithm usually results in many redundant and overlapped subpathways. The minimal-spanning tree is a simple data structure that is frequently used to represent tightly related nodes in a graph. It is more appropriate to represent various subpathways than the k-clique structure, especially in sparse-pathway networks. We applied the sub-SPIA method to the colorectal cancer and lung cancer datasets, and our results demonstrate that the proposed method can identify more disease-related pathways than SPIA, DEgraph, Clipper, and Pathiways. Furthermore, we find that most of the pathways identified by sub-SPIA have a high degree and are tightly connected within the entire pathway network. This result reveals that diseases may result from the synergic interactions of a group of related PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19748643 pathways. Results There are 137 signaling pathways in KEGG. To deduce pathway significance, we used a significance threshold of 1% on the p-values corrected for false discovery rate. For both subSPIA and SPIA, the FDR-adjusted p-values PG which combine the enrichment and perturbation p-values, were computed from the nominal pvalues by using the R function “p.adjust.” We present herein the significantly enriched pathways by applying sub-SPIA and SPIA to CRC and lung cancer datasets. The deregulation of the notch signaling pathway was observed in colorectal and other forms of cancer. NOTCH is the center of the subpathway identified by sub-SPIA. The abnormal expression of NOTCH and its upstream gene NUMB would lead to the dysfunction of many downstream genes. The Notch signaling pathway is involved in regulating stem-cell hierarchy and determining cell fate. A recent study indicates that PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19748686 inhibiting prolactin can completely abrogate the Notch signaling pathway and may provide a novel target for therapeutic intervention. Elafin is a protease inhibitor with antiba