TheJournalofClinicalInvestigationReseaRchaRticle1839jci.orgVolume125Number5May2015IntroductionOsteosarcoma,themostcommonprimarymalignantbonetumor,occursmostfrequentlyinchildrenandadolescentsandhasastrongtendencytometastasize.Pulmonarymetastasisisthemaincauseofmedicaltherapyfailureanddeathinosteosa-rcomapatients.Despiteanintensivesearchfornewtherapeuticstrategies,survivalhasnotimprovedoverthepast2decades(1).Giventhatcontrollingmetastasisisthekeytoimprovingsurvival,thereisanurgentneedtoinvestigatetheunderlyingmecha-nismsofosteosarcomametastasisandtodevelopmoreeffectiveapproachestosuppresslungmetastasis.Itiswidelyacceptedthatthemultistepprocessofcancerevo-lutionisdrivenbybothgeneticandepigeneticabnormalities(2).Unlikegeneticalterations,epigeneticchangesarepotentiallyrevers-ible,makingthemattractiveandpromisingtargetsfortherapeuticintervention.PreviousstudiesindicatedthatabnormalDNAmeth-ylation,amajorepigeneticmodification,isinvolvedinthedysreg-ulationofthecellcycleandapoptosisaswellasintheproliferationanddifferentiationofosteosarcoma(3,4).However,theepigeneticmechanismsofosteosarcomametastasisremainlargelyunknown.Iroquoishomeobox1(IRX1),amemberoftheIroquoishomeoboxfamilyoftranscriptionfactors,playsacrucialroleinembryonicdevelopment(5).Recently,IRX1wasidentifiedasapotentialtumor-suppressorgeneinheadandnecksquamouscellcarcinoma(HNSCC)andgastriccancer(6,7);however,furthereffortsarerequiredtodeterminetheexactfunctionofIRX1inthedevelopmentofothercancers,includingosteosarcoma.IRX1isinvolvedinlimbdevelopment(8)andtheetiologyofkyphoscoli-osis(9),suggestingthataberrantIRX1expressionmaycontributetoabnormalboneformation.Moreover,againofchromosome5p15.33(chromosomallocationofIRX1)hasbeenfrequentlydetectedinosteosarcomacelllines(10).Therefore,theroleofIRX1inthepathogenesisofosteosarcomaisofinterest.Chemokine(C-X-Cmotif)ligand14(CXCL14),alsoknownasBRAK,isasmallcytokinebelongingtotheCXCchemokinefamily(11),andthegeneencodingCXCL14iscommonlyrecognizedasatumor-suppressorgene(12–14)....
