PTHrP and SPARC expressions in human colorectal cancer: An in silico analysis

CARRIERE, P.; NOVOA DIAZ, M.; LOPEZ MONCADA, F.; ZWENGER, A.; CONTRERAS, H.; CALVO, N.; GENTILLI, C.

ANNALS OF ONCOLOGY

OXFORD UNIV PRESS

Año: 2021 vol. 32

0923-7534

Background: PTHrP isaparaneoplasticfactorinvolvedintheprogressionandtheacquisitionoftheaggressivebehaviorofdifferenttypesoftumors.Employinginvitroand invivomodelsofcolorectalcancer(CRC),ourresearchgroupobservedthatPTHrP promotescellsurvival,proliferation,migration,angiogenesis,epithelialtomesenchymal transition(EMT)program,cancerstemcell(CSC)phenotype,andchemoresistancethroughdifferentsignalingpathways.Recently,inHCT116cellsderived fromCRCwefoundthatPTHrPactsincreasingSPARCproteinexpression,arelevant proteininvolvedinCRCprogression.Moreover,SPARCtreatmentonHCT116cells potentiatedPTHrPeffects.Invivomodel,PTHrPalsoincreasedSPARCexpres-sion. Basedonthese findings, theaimofthisworkisexploretheclinicalrelevanceofPTHrP andSPARCtumorexpressioninhumanCRCusinginsilicoanalysis.Methods: Cytoscape 3.8.2stringAppwasemployedtovisualizemolecularnetworksfrom theSTRINGdatabaserelatedtoCRC,andproteinsassociatedwithprognosticfactors wereselectedtoanalysis.UsingSTRINGEnrichmentApp,theproteinsnet-works (PN)mergedwerecomparedtoestablishenrichment.Finally,insilicotoolandonline datasets(GEPIA2andSTRING11.0)wereusedtoexploretheassociationofPTHrP andSPARCandtheirprognosticvaluein362CRChumansamples.Results: In GEPIA2database,asignificant correlationbetweentheexpressionsofPTHrP andSPARCinCRCwasobserved(p-value¼0.01). Also,SPARCexpressionwashigherinCRCrespecttocolorectalnormalsamples(p-value¼0.01). Inthesameway,SPARC expressionwassignificantly higherinCRCadvancedthaninearlydisease.EmployingSTRING11.0database,weobservedastrongassociationbetweenPTHrPand severaloncogenicmarkers(CDH2,CD44,VIM,amongothers)thatpreviouslywere evaluatedinvitrobyuslinkedthroughSPARCwithaProtein-Proteininteractionenrichment(p-value0.95).ThisPNwasmergedwiththePNobtainedfromthesearch?colorectal cancer? with ahighdiseasescore(SD> 3.2). Fromthisanalysis,VEGFAwasemerged asacentralnexusbetweenPTHrPandSPARCproteins.Finally,GEPIA2wasused toevaluatethesurvivalrateinCRCpatientsthatexpressPTHrPand/orSPARC.No significant impactinoverallsurvivalwasfoundtakenaccounthighorlowexpressionofeachprotein.Conclusions: In CRCtumorsamples,astrongrelationshipbetweenPTHrPandSPARCexpressionwasfound,suggestingthatbothproteinscouldbeinvolvedinthepro-gression ofthedisease.DespiteVEGFAwasalsoassociatedwithPTHrP/SPARC,morestudies arenecessarytoevaluatetheirclinicalrelevancy.Legal entityresponsibleforthestudy: The authors.Funding: Agencia NacionaldePromociónCientífica yTecnológica(PICT-2013-1441),Consejo NacionaldeInvestigacionesCientíficas yTécnicas(PIP11220150100350),Instituto NacionaldelCáncer(AsistenciaFinancieraIII-2016-2017,RESOL-2016-1006-E-APN-MS),UniversidadNacionaldelSur(PGI:24/B230;PGI:24/B303),Argentina.Disclosure: All authorshavedeclarednoconflicts ofinterest.