An Integrative -omics Approach to Identify Functional Sub-Networks in Human Colorectal Cancer 英文参考文献.docVIP

AnIntegrative-omicsApproachtoIdentifyFunctional Sub-NetworksinHumanColorectalCancer RodK.Nibbe1,2*,MehmetKoyutu¨rk1,3,MarkR.Chance1,4 1Center for Proteomics Bioinformatics, Case Western Reserve University, Cleveland, Ohio, United States of America, 2Department of Pharmacology, Case Western ReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica,3DepartmentofElectricalEngineeringComputerScience,CaseWesternReserveUniversity,Cleveland, Ohio,UnitedStatesofAmerica,4DepartmentofPhysiologyBiophysics,CaseWesternReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica Abstract Emerging evidence indicates that gene products implicated in human cancers often cluster together in ‘‘hot spots’’ in protein-protein interaction (PPI) networks. Additionally, small sub-networks within PPI networks that demonstrate synergistic differential expression with respect to tumorigenic phenotypes were recently shown to be more accurate classifiersofdiseaseprogressionwhencomparedtosingletargetsidentifiedbytraditionalapproaches.However,manyof thesestudiesrelyexclusivelyonmRNAexpressiondata,ausefulbutlimitedmeasureofcellularactivity.Proteomicprofiling experiments provide information at the post-translational level, yet they generally screen only a limited fraction of the proteome.Here,wedemonstratethatintegrationofthesecomplementarydatasourceswitha‘‘proteomics-first’’approach canenhancethediscoveryofcandidatesub-networksincancerthatarewell-suitedformechanisticvalidationindisease. WeproposethatsmallchangesinthemRNAexpressionofmultiplegenesintheneighborhoodofaprotein-hubcanbe synergistically associated with significant changes in the activity of that protein and its network neighbors. Further, we hypothesizethatproteomictargetswithsignificantfoldchangebetweenphenotypeandcontrolmaybeusedto‘‘seed’’a search for small PPI sub-networks that are functionally associated with these targets. To test this hypothesis, we select proteomictargetshavingsignificantexpressionchangesinhumancolorectalcancer(CRC)from