Biological Networks and Pathway Analysis

Anton A. Buzdin, Vladimir Prassolov, Alex A. Zhavoronkov, Nikolay M. Borisov

We propose a biomathematical approach termed OncoFinder (OF) that enables performing both quantitative and qualitative analyses of the intracellular molecular pathway activation. OF utilizes an algorithm that distinguishes the activator/repressor role of every gene product in a pathway. This method is applicable for the analysis of any physiological, stress, malignancy, and other conditions at the molecular level. OF showed a strong potential to neutralize background-caused differences between experimental gene expression data obtained using NGS, microarray and modern proteomics techniques. Importantly, in most cases, pathway activation signatures were better markers of cancer progression compared to the individual gene products. OF also enables correlating pathway activation with the success of anticancer therapy for individual patients. We further expanded this approach to analyze impact of micro RNAs (miRs) on the regulation of cellular interactome. Many alternative sources provide information about miRs and their targets. However, instruments elucidating higher level impact of the established total miR profiles are still largely missing. A variant of OncoFinder termed MiRImpact enables linking miR expression data with its estimated outcome on the regulation of molecular processes, such as signaling, metabolic, cytoskeleton, and DNA repair pathways. MiRImpact was used to establish cancer-specific and cytomegaloviral infection-linked interactomic signatures for hundreds of molecular pathways. Interestingly, the impact of miRs appeared orthogonal to pathway regulation at the mRNA level, which stresses the importance of combining all available levels of gene regulation to build a more objective molecular model of cell.