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DickkopfsandWnt/β-cateninsignallinginlivercancerSarwatFatima,NikkiPLee,JohnMLukSarwatFatima,NikkiPLee,DepartmentofSurgery,TheUni-versityofHongKong,HongKong,ChinaJohnMLuk,DepartmentofPharmacologyandSurgery,Na-tionalUniversityHealthSystem,Singapore117597,SingaporeJohnMLuk,CancerScienceInstituteofSingapore,NationalUniversityofSingapore,Singapore117456,SingaporeJohnMLuk,InstituteofMolecularandCellBiology,A*STARSingapore,Singapore138673,SingaporeAuthorcontributions:FatimaSdesignedandwrotethemanu-script;LeeNPandLukJMedited,advisedandsupervisedthiswork.
Correspondenceto:JohnMLuk,Professor,CancerScienceInstituteofSingapore,NationalUniversityofSingapore,Singa-pore117456,Singapore.
jmluk@nus.
edu.
sgTelephone:+65-65164516Fax:+65-68737690Received:June13,2011Revised:July7,2011Accepted:July14,2011Publishedonline:August10,2011AbstractLivercanceristhefifthandseventhmostcommoncauseofcancerinmenandwomen,respectively.
Wnt/β-cateninsignallinghasemergedasacriticalplayerinboththedevelopmentofnormalliveraswellasanoncogenicdriverinhepatocellularcarcinoma(HCC).
Basedonthecurrentunderstanding,thisarticlesummarizesthepossiblemechanismsfortheaberrantactivationofthispathwaywithspecificfocusonHCC.
Furthermore,wewilldiscusstheroleofdickkopfs(DKKs)inregulatingWnt/β-cateninsignalling,whichispoorlyunderstoodandunderstudied.
DKKsareafamilyofsecretedpro-teinsthatcompriseatleastfourmembers,namelyDKK1-DKK4,whichactasinhibitorsofWnt/β-cateninsignalling.
Nevertheless,notallmembersantagonizeWnt/β-cateninsignalling.
Theirfunctionalsignificanceinhepatocarcinogenesisremainstobefurthercharacter-izedforwhichthesestudiesshouldprovidenewinsightsintotheregulatoryroleofDKKsinWnt/β-cateninsignal-linginhepaticcarcinogenesis.
Becauseoftheimportantoncogenicroles,thereareanincreasingnumberoftherapeuticmoleculestargetingβ-cateninandtheWnt/β-cateninpathwayforpotentialtherapyofHCC.
2011Baishideng.
Allrightsreserved.
Keywords:Dickkopf;Hepatocellularcarcinoma;Tu-mourigenesis;Wnt/β-cateninsignallingPeerreviewers:StevenARosenzweig,PhD,Professor,Depart-mentofCellandMolecularPharmacologyandExperimentalTherapeutics,MedicalUniversityofSouthCarolina,173AshleyAvenue,Charleston,SC29425,UnitedStates;EijiMiyoshi,MD,PhD,Professor,DepartmentofMolecularBiochemistryandClinicalInvestigation,ProfessorandChairman,OsakaUni-versityGraduateSchoolofMedicine,565-08711-7Yamada-okaSuita,JapanFatimaS,LeeNP,LukJM.
DickkopfsandWnt/β-cateninsig-nallinginlivercancer.
WorldJClinOncol2011;2(8):311-325Availablefrom:URL:http://www.
wjgnet.
com/2218-4333/full/v2/i8/311.
htmDOI:http://dx.
doi.
org/10.
5306/wjco.
v2.
i8.
311hepatocellularcarcinomaANDTHEUNMETMEDICALNEEDSLivercancerranksthefifthmostcommoncancerinmenandthesecondleadingcauseofcancer-relateddeath.
Inwomen,itistheseventhmostfrequentcancerandsixthleadingcauseofcancerdeath[1].
Hepatocellularcarci-noma(HCC)isthemostcommonprimarymalignancyofliver.
MenarethreetimesmorelikelytodevelopHCCthanwomenandtheincidenceincreaseswithage[2].
HCCisprevalentinAsiaandAfrica,butrecentlyitisontheriseintheWesternworldduetoanincreaseinhepatitisCvirus(HCV)infection[3].
RiskfactorsforHCCincludechronichepatitisBvirus(HBV)andHCVinfections,cirrhosis,chronicalcoholabuse,aflatoxiningestion,non-alcoholicsteatohepatitisandothermetabolicliverdiseases[4,5].
MuchofHCCoccursinthebackgroundofcirrhosis.
About80%-90%ofpatientswithcirrhosisgoontodevelopHCCeventuallyandtheremaining10%-20%ofcasesdevelopHCCwithoutcirrhosis.
Fur-thermore,HBVandHCVinfectionsincreasetheriskofdevelopingcirrhosisandlaterHCC.
AmongtheHCCREVIEWWorldJClinOncol2011August10;2(8):311-325ISSN2218-4333(online)2011Baishideng.
Allrightsreserved.
OnlineSubmissions:http://www.
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com/2218-4333officewjco@wjgnet.
comdoi:10.
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v2.
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311WorldJournalofClinicalOncologyWJCO311August10,2011|Volume2|Issue8|WJCO|www.
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comFatimaSetal.
DKKsandWnt/β-cateninsignallingcaseswithcirrhosis,HCVinfectionhasbeenidentifiedin27%-73%andHBVinfectionin12%-55%[6,7].
HCCsuffersfromahighmortalityrateduetolackofeffectivediagnosticmethodsforearlydetectionaswellaslackoftreatmentoptionsespeciallyforthosewithad-vanceddiseaseconditions.
DespitevigorousattemptstoscreenforearlyHCCbycommonsurveillancetechniquesusingserumα-fetoprotein(AFP)andultrasoundexami-nation,earlyHCCisasymptomaticandmostHCCcasesarepresentedlatewhensurgicaltreatmentsarenotame-nable[8].
Althoughsurgicalresectionremainsthetreatmentofchoiceforpatientswithwell-preservedliverfunction,itisassociatedwithahighriskofpost-operativecompli-cationsandtumourrecurrence[7].
LivertransplantationisanothertreatmentoptionforearlyHCCbutthisislimitedbytheshortageofsuitablelivergrafts[9].
OthersurgicaltreatmentsforHCCincluderadio-frequencyablation(RFA),microwaveablation(MWA)andtrans-catheterarterialchemoembolization(TACE).
RFAandMWAtechniquesutilisehighfrequencyradio-wavesandmicro-waves,respectively,tokilltumourtissuesbyheat.
Althoughseveralstudieshavereportedbetterdisease-freesurvivalandalowerfrequencyofrecurrenceaftersurgicalresectioncomparedtoRFA[10,11],othersreportbetteroverallsurvivalanddisease-freesurvivalforHCCpatientswithmulti-nodulartumoursfollowingRFA[12].
Recently,Simoetal[13]reportednodifferenceregardingtheefficaciesofMWAandRFAprocedures.
TACEisroutinelyperformedonHCCpatientswhoarenoteli-gibleforsurgicalresectionortumourablationtechniques.
However,thesurvivalbenefitsofTACEdependoncare-fulpatientselection.
Patientswithmulti-nodularHCC,withoutvascularinvasionandnoextrahepaticmetastasesshowabetter2-yearsurvival(63%)afterTACEthanHCCpatientswithvascularinvasionundergoingTACE(31%)[14,15].
However,tumourrecurrenceisanimportantlimitationtoanyoftheHCCtreatments,andthus,un-derstandingthemolecularbiologyofHCCiscrucialforthedevelopmentofnoveltherapies.
Inrecentyears,studieshaveshedlightontheclinicalimplicationsofsignallingpathwaysinHCC,includingtheRas/Raf/MEK/ERKpathway[16],thePI3K/Akt/mTORpathway[17],theJNKpathway[18]andtheNF-κBpath-way[19].
Apromisingapproachwouldbetoidentifymo-lecularpathwaysresponsibleforinitiatingandsustainingHCCastargetsforHCCtherapy.
ThecanonicalWnt/β-cateninsignallingpathwayisanothersuchoncogenicpathway,whichisfrequentlyactivatedinHCCandisreportedtoplayapivotalroleintumourigenesis[20].
ThisarticlereviewsthecanonicalWnt/β-cateninsignallingpathwayanditsinvolvementinHCCdevelopment.
Inad-dition,antagonistsofthispathwayandtheirimplicationsinHCCaredescribedanddiscussed.
Fromthispriorknowledge,wehopetoidentifymembersofthispathwaythatcouldserveaspotentialtargetsforHCCtherapy.
OVERVIEWOFWNT/β-CATENINPATHWAYTheWnt/β-cateninpathwayisawell-conservedpath-waythatisimportantinembryonicdevelopment,cellproliferation,survival,regenerationandself-renewal[21-23].
Likewise,agreatdealofunderstandinghasbeenachievedbystudyingpathologicalspecimensandusingmousemodelsofliverdiseasestounderstandtheaberrationsofthispathwayinliverdiseasesrangingfromhepatitistoHCC[24-26].
Basedontheseearlierstudies,theWnt/β-cateninpathwayisacentralplayerinmaintainingliverhealthandisdysregulatedinhepaticcancers,whichmakesitanattractivecandidateforpotentialtherapiesofHCC.
Inanunstimulatedcell,endogenousβ-cateninisfoundattheadherensjunctions,whereitinteractswithcompo-nentsofthecadherin-associatedproteincomplexestoconfercell-celladhesionfunctions[27,28].
Ontheotherhand,surplusβ-catenininthecytoplasmisdegradedbytheac-tionofadestructioncomplexwhichconsistsofglycogensynthasekinase3β(GSK3β),Axin,adenomatouspolypo-siscoli(APC)andcaseinkinaseIα(CKIα)[29].
β-Cateninisfirstphosphorylatedatserine-45(Ser45)byCKIαtofurtherprimeitforphosphorylationbyGSK3βatSer33,Ser37andthreonine-41(Thr41).
Thephosphorylatedβ-cateninisthenubiquitinatedbyβ-transducinrepeat-containingprotein(β-TrCP)andsubsequentlydegradedbytheproteasome[30](Figure1A).
Maheretal[31]reportedthatβ-cateninphosphorylatedatSer45andnotatSer33/Ser37/Thr41ispredominantlylocatedinthenucleus,whereasβ-cateninphosphorylatedatSer33/Ser37/Thr41ismostlylocalizedtothecytoplasm.
Thisspatialsepara-tionofβ-cateninsuggeststhatphosphorylationatSer45andatSer33/Ser37/Thr41isnotnecessarilycoupled.
ItmayalsoimplythatphosphorylationatSer45byCKIαservesanotherfunction,yettobedelineated,otherthanprimingβ-cateninforfurtherphosphorylationbyGSK3β.
Fordiseasedcondition,theWnt/β-cateninsignallingpathwayisactivateduponbindingofWnttooneofthemembersofthefrizzled(FZD)familyandtolow-densitylipoproteinreceptor-relatedprotein5(LRP5)orLRP6.
TheFZDrecruitsdishevelled(Dvl)totheplasmamembrane,whichinturnrecruitsAxinandGSK3βtoLRP5/LRP6[32].
TheintercellulardomainofLRP5/LRP6containsfivereiteratedPPPSPxSmotifs,whichareduallyphosphorylatedbyGSK3βandCKIα[33].
Thephosphor-ylationofLRP5/LRP6disruptstheformationofthedestructioncomplex,therebypreventingGSK3βfromphosphorylatingβ-catenin.
Therefore,β-cateninisnotdegradedandaccumulatesinthecytoplasmfromwhereittranslocatestothenucleus.
IntheabsenceofWnt,T-cellfactor(TCF)/lymphoidenhancerfactor(LEF)re-pressesgeneexpressionbyinteractingwithco-repressorGroucho,whichpromoteshistonedeacetylationandchromatinmodellinginthenucleus[34].
Nuclearaccumu-lationofβ-catenindisplacesGrouchofromTCF/LEFandrecruitsothertranscriptionalco-activators,e.
g.
CREBbindingprotein(CBP),forupregulationoftargetgenesthatareimplicatedincellproliferation,anti-apoptosis,andangiogenesis,suchascyclinD1[35](Figure1B).
Recentstudieshavesupportedreceptor-mediatedendocytosisforWntinducedsignalling[36,37].
Specifically,Wnt3awasshowntoinducecaveolin-dependentinternalizationof312August10,2011|Volume2|Issue8|WJCO|www.
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comLRP6,whichwouldinturnrecruitAxintoLRP6phos-phorylatedbyGSK3βandCKIα,andtherebyleadtoβ-cateninaccumulation.
Thus,caveolinplaysacriticalroleinactivatingWnt/β-cateninsignalling[37].
Veryrecently,Chairoungduaetal[38]showedanovelmechanismofreducingcytoplasmicβ-cateninlevelsindependentlyofGSK3βphosphorylationorubiquitina-tionbyexportingβ-cateninoutofthecellviaexosomes.
Exosomesarevesiclesthatforminsideendosomesandthevesiclesarethensecretedwhentheendosomesfusewiththeplasmamembrane[39].
Theseexosomesareen-richedinE-cadherinandtetraspaninproteins(CD9andCD82).
Expressionofthesetetraspaninswasshowntodecreaseβ-cateninproteinlevels,butfurtherexperimentsshowedthatE-cadherinwasalsonecessaryforβ-cateninsecretioninexosomes.
ThemolecularmechanismfortheinclusionofCD9,CD82andE-cadherininexosomeswarrantsfurtherinvestigation.
Furthermore,howthesetetraspaninsinduceexosomeformationremainstobecharacterized.
Althoughmuchremainstobeinvestigated,thisimportantandnovelmechanismoffersanalterna-tiveroutefortheregulationofWnt/β-cateninactivity,furtherhighlightingthesignificanceofkeepingtheWnt/β-cateninpathwayundercheck.
ABERRANTWNT/β-CATENINSIGNALLINGINHCCRoleofaberrantβ-cateninactivationinHCCHCCisoneofthecancerswithahighrateofdys-regulationintheWnt/β-cateninpathwayandalthough40%-70%[40-43]ofHCCpatientshavetumourswithhighlevelsofβ-cateninaccumulation,thereislittleagreementontheuseofβ-catenininprognosis.
Nuclearaccumula-tionofβ-cateninisstronglyassociatedwithβ-cateninmutations[41].
Amajorityofβ-cateninmutationsinHCCaremissensemutationsoccurringatexon3.
Thisregionisresponsibleforphosphorylationandubiquitinationofβ-catenin,andtherefore,mutationinthisregionresults13August10,2011|Volume2|Issue8|WJCO|www.
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comAxinAPCDKK1,DKK2,DKK4LRP5/6KremenWntsFRPWIFFZDCytoplasmPlasmamembraneHDPR1Prickle-1Dvlb-cateninCKIaDKK3b-TrCPGSK3bpppppppUbUbb-cateninpb-catenindegradationbyproteasomeTCF/LEFGrouchoNucleusLRP5/6APCWntCytoplasmPlasmamembraneb-cateninGSK3bpTCF/LEFNucleusFZDAxinDvlpb-cateninb-cateninb-cateninb-cateninCBPCKIaNLKc-Myc,CyclinD1,DKK1,etc.
miR-181miR-375BAFigure1Wnt/β-cateninsignallingintheabsenceandpresenceofWntstimulus.
A:Wnt/β-cateninsignallingisregulatedbyseveralantagoniststopreventtheformationoffrizzled(FZD)-Wnt-low-densitylipoproteinreceptor-relatedprotein5/6(LRP5/6)complex.
Secretedfrizzled-relatedprotein(sFRP)andWntinhibitoryfactor(WIF)binddirectlytoWnt,whereasdickkopfs(DKKs)bindtoLRP5/6.
Furthermore,humanhomologueofDapper(HDPR1)andPrickle-1inhibittheactionofdishevelled(Dvl).
IntheabsenceofWntstimulus,β-cateninisfirstprimedforphosphorylationbycaseinkinaseIα(CKIα)followedbyphosphorylationbyglycogensynthasekinase3β(GSK3β)atthreeresidues.
Thephosphorylatedβ-cateninistargetedforubiquitinationbyβ-transducinrepeat-containingprotein(β-TrCP)andissubsequentlydegradedbytheproteasome.
Inthenucleus,T-cellfactor(TCF)/lymphoidenhancerfactor(LEF)repressestranscriptionoftheWnt/β-cateninpathwaytargetgenesbyinteractingwithco-repressorGroucho;B:WntbindstoandactivatesFZDandLRP5/6receptors.
DvlisrecruitedtotheplasmamembraneandbindstoFZD.
ThisresultsintherecruitmentofAxinandGSK3βtoLRP5/6.
LRP5/6isthenphosphorylatedbyCKIαandGSK3β,resultinginaninactivationofthedestruc-tioncomplexandleadingtoβ-cateninaccumulationinthecytoplasm.
β-cateninthensubsequentlytranslocatestothenucleuswhereitbindswithTCF/LEFandotherco-activatorse.
g.
CREBbindingprotein(CBP)tomediatetranscriptionofgenesandmicroRNAsresponsibleforproliferationandgrowth.
APC:Adenomatouspolypo-siscoli;NLK:Nemo-likekinase;p:Phosphorylated;Ub:Ubiquitinated.
FatimaSetal.
DKKsandWnt/β-cateninsignallinginstableβ-cateninthatconsequentlyaccumulatesinthenucleus.
Maoetal[44]associatednuclearβ-cateninaccu-mulationtoβ-cateninmutation,non-invasiveformoftumourandgoodprognosis.
HCCtumourswithmutantnuclearβ-cateninresultedinabetter5-yearsurvivalthanHCCtumourswithwild-typenuclearβ-cateninac-cumulation.
Thisissuggestiveofthefactthatwild-typeβ-cateninaccumulationandmutantβ-cateninaccumula-tionarenotequivalent.
Furthermore,inthisstudyof37HCCtumourswithnuclearmutantβ-cateninaccumula-tion,19mutationsoccurredatthesitesofGSK3βphos-phorylation(Ser45,Ser33,Ser37andThr41),3tumourshadβ-catenindeletions,and15mutationswerereportedatothersites.
However,severalstudieshavecorrelatednuclearβ-cateninaccumulationtotumourprogressionandpoorprognosis[43,45,46].
Kondoetal[46]reportedthatβ-cateninaccumulationandβ-cateninmutationdonotoccurearlyinhepatocarcinogenesis,butcouldbeas-sociatedwithmalignantprogressionofHCC.
Similartothesefindings,Inagawaetal[45]observedpoorprognosisinHCCpatientswithnuclearβ-cateninaccumulationingradeⅢHCCtumoursandnotingradeⅠorgradeⅡHCCtumours.
Furthermore,nuclearβ-cateninac-cumulationinHCChasalsobeencorrelatedtoKi67(amarkerfortumourcellproliferation),suggestingthatβ-cateninpromotestumourprogression[43].
Thediscrepancyinβ-cateninaccumulationandHCCprog-nosiscouldbeduetothetypeofβ-cateninmutations.
Functionalstudiesontheroleofdifferentmutationsonβ-cateninstabilitymayofferinsightsintomechanismsinvolvedinβ-cateninregulation.
Otherreasonsforthediscrepancymayincludetumourhistologyandthesizeofthetumour.
Additionally,thepresenceofβ-cateninmutationsdemonstratesdifferentphenotypicalfeaturesinHCC.
Cieplyetal[47]reportedthatHCCtumourshar-bouringamissensemutationatexon3exhibitamoreaggressivephenotypeandmaydevelopHCCwithoutcirrhosiscomparedtoHCCwithnon-mutatedβ-catenin.
Thus,β-cateninmutationsmayserveasanindependentriskfactorforthedevelopmentofHCCintheabsenceofcirrhosis.
GreatertumoursizehasalsobeenreportedinHCCtumourswithβ-cateninmutationsascomparedtothosewithoutmutationinβ-catenin[48].
Somestud-ieshavecorrelatedcytoplasmicβ-catenin(non-nuclearβ-catenin)withpoorcellulardifferentiation,largetu-moursize(>5cmindiameter)andshortdisease-freesurvival[41].
Forreasonsnotyetelucidated,HCV-associat-edHCChasagreaterfrequencyofβ-cateninmutationsthantheHBV-associatedtype[42].
Severalstudiesontransgenicanimalmodelshaveshownthatoverexpressionofmutantorstableformsofβ-cateninonitsownisnotsufficienttoinducetumoursinliver[49-51].
However,deletionofAPCinmiceresultsinhepatomegaly,hepatocytehyperplasiaandrapidmortal-ity[52].
Thus,β-cateninmutationsoraccumulationmayco-operatewithothergenesorsignallingpathwaystoresultinhepatocarcinogenesis.
However,itisalsoimportanttotakeintoaccountthefunctionalrolesofAPCthatareindependentofβ-catenin,e.
g.
APCmaintainsepithelialintegrityinnon-transformedmousemammaryepithelialcells[53]anditregulatescellcycleprogressionthroughtheSphasebyinhibitingDNAreplicationviadirectinterac-tionwithDNAincoloncancercelllines[54].
NewmousemodelsarerequiredthatmimicirregularWnt/β-cateninpathwaytounderstandtheroleofthispathwayaswellasitstherapeuticimplications.
Wnt/β-cateninpathwaytargetgenesinHCCSeveralβ-catenintargetgenesinassociationwithlivercarcinogenesiswereidentifiedbytheirhighexpressioninchronicliverdiseasesandHCC.
However,theirspecificroleinhepatocarcinogenesisremainsunknown.
Fre-quentamplificationandoverexpressionofc-MycandcyclinD1inHCCisassociatedwithcytoplasmicandnuclearβ-cateninaccumulationalongwithpoorprog-nosis[55-61].
However,thereislittleconsensusonwhethertheoverexpressionofc-MycandcyclinD1isaresultofmutationsinβ-catenin.
Cadoretetal[49]didnotreportc-MycorcyclinD1inductionintheliveroftransgenicmicethatexpressamutantformofβ-catenin,althoughsuchmicedidexhibithepatomegalyandmarkedhepa-tocellularproliferation.
Incontrast,deLaCosteetal[62]reportedactivatingsomaticmutationsinβ-cateninin50%ofhepatictumoursinc-Myctransgenicmice.
InadditiontocyclinD1andc-Myc,severalothergeneshavebeenidentifiedasdownstreammoleculesoftheWnt/β-cateninpathwayinHCC(Table1).
ExpressionofthesegeneswasdiscoveredinHCCtransgenicmiceorinHCCtissuesexhibitingaccumulationofwildtypeormutatedβ-catenin.
Forexample,glutaminesynthetaseandorphanG-protein-coupledreceptorarefrequentlyoverexpressedinHCCwithmutationinβ-catenin[63,64].
Furtherstudiesarewarrantedtounderstandwhethermutatedorstableβ-cateninresultsintranscriptionofdifferenttargetgenes,andifsilencingthesetargetgenesaffectsaberrantWnt/β-cateninpathwayinanegativefeedbackmanner.
Moreimportantly,cantheexpressionofβ-catenintargetgenesinHCC,e.
g.
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comTable1DownstreammoleculesoftheWnt/β-cateninpathwaywithoverexpressioninhepatocellularcarcinomaGeneRef.
c-Myc[159]CyclinD1[57]Dickkopf1[126]Epidermalgrowthfactorreceptor[51]Glutaminesynthetase[63]Glutamatetransporter[63]Leukocytecell-derivedchemotaxin2[160]Ornithineaminotransferase[63]OrphanG-protein-coupledreceptor[64]Regeneratingislet-derived1α[161]Regeneratingislet-derived3α[161]FatimaSetal.
DKKsandWnt/β-cateninsignallingAlterationsofWnt/β-cateninpathwaycomponentsinHCCAccumulationofβ-catenincanalsooccurintheabsenceofβ-cateninmutationorduetoaberrantexpressionofothermembersoftheWnt/β-cateninpathway[65].
Table2summarizestheaberrantexpressionofWnt/β-cateninsig-nallingcomponentsinHCC.
WntandFZDTheWntfamilyiscomposedofnineteensecretedgly-coproteins[66].
TheybindtotheextracellulardomainofFZDsandactivatetheWnt/β-cateninpathway[67].
TendifferentFZDgeneshavebeenidentifiedinmammalsandallofthemencodeseventransmembranerecep-tors[68].
Wnt1isupregulatedinHCCtissuescomparedtoadjacentnon-tumourtissuesanditsexpressionhasbeenassociatedwithtumourrecurrence[69].
Furthermore,threeotherWntgenes(Wnt3,Wnt4andWnt5A),andthreeFZDgenes(FZD3,FZD6andFZD7)arealsoup-regulatedinHCCtissuesandpreneoplasticperitumouraltissuesascomparedwithnormallivertissues,suggestingthattheiroverexpressionmaybeanearlyeventinhepa-tocarcinogenesis.
However,onlytheoverexpressionofFZD7hasbeenassociatedwithnuclearand/orcytoplas-micaccumulationofβ-catenininHCC[70-72].
GSK3β,CKIα,AxinandAPCTherearenoreportsofmutationsoraberrantexpressionofCKIαinHCC.
Afewstudieshavereportedoverex-pressionofphosphorylatedGSK3β(phospho-GSK3β,inactiveformofGSK3β)inHCCcellsandtissues,butthishasnotbeenfoundtobeassociatedwithβ-cateninaccumulation[73,74].
TherearetwoAxingenes.
Axin1isconstitutivelyexpressed,whereasAxin2(alsoknownasAxilorCon-ductin)isinducedbyWnt/β-cateninsignallingandtakespartinanegativefeedbackloop[75].
Kimetal[76]recentlyobservedreducedAxin1expressiononlyinHCCtissuesandnotincirrhoticnodules,implyingthatitsreducedex-pressionisindependentofcirrhosis.
TherearecurrentlynoreportsofAxin2expressioninHCC.
However,Axin1andAxin2mutationsarerareinHCCoccurringinonly10%and3%ofHCCcases,respectively[48,77,78].
AmajorityofthesemutationsareframeshiftornonsensemutationsandmorethanhalfofHCCcaseswithAxin1orAxin2mutationshaveβ-cateninaccumulationinthecytoplasmornucleus[77].
Interestingly,Zucman-Rossietal[79]recentlydemonstratedthatthelossofAxin1functionisnotequivalenttogain-of-functionofβ-catenin,suggestingthatAxin1couldalsobeparticipatinginotherpathwaysinHCC.
APCmutationsareveryrareinHCCandpromotermethylationhasbeenreportedtoplayanimportantroleinitsinactivation[80].
DvlandPeptidyl-prolylcis/transisomeraseDvlisapositiveregulatorofWnt/β-cateninsignallingandpreventsGSK3βfromphosphorylatingβ-catenin,leadingtoβ-cateninstabilisation[81].
ItsoverexpressionhasbeenshowntobecriticalinWnt/β-cateninsignal-lingactivationandβ-cateninaccumulationinvariouscancersincludingHCC[82].
TwoinhibitorsofDvlhavebeenidentifiedincludingPrickle-1[82]andhumanhomo-logueofDapper[83]bothofwhicharereducedinHCCandtheirreducedexpressionhassignificantassociationwithβ-cateninaccumulation.
Peptidyl-prolylcis/transisomerase(PIN1)isanotherpositiveregulatoroftheWnt/β-cateninpathwayandfunctionsbyinhibitingtheinteractionbetweenβ-cateninandAPC[84].
Itisalsoover-expressedinmorethan50%ofHCCcasesandthishasbeencorrelatedtoincreasedβ-cateninandcyclinD1ac-cumulation.
Furthermore,β-cateninmutationandPIN1overexpressionaremutuallyexclusiveeventsinHCC,suggestingthatmechanismsotherthanβ-cateninmuta-tionalsoleadtoβ-cateninstabilisationandaccumula-tion[65].
TCF/LEFThehumanTCF/LEFfamilyconsistsoffourmembers,LEF-1,TCF-1,TCF-3andTCF-4,andallmemberscon-tainaconservedhighmobilitygroupboxtobendDNAtoallowbindingoftranscriptionfactors,aβ-catenin-bindingdomaintobindβ-cateninandatranscriptionre-pressiondomaintorecruitco-repressorslikeGroucho[85].
Whenβ-catenintranslocatestothenucleus,itbindstotheβ-catenin-bindingdomainofTCF/LEFandactivatestranscriptionoftargetgenes.
TheTCF/LEFfamilyhasseveralsplicedformswithunknownfunctionalsignifi-canceanditissuggestedthattheymayactivatepreferen-tialgenes[86].
InHCC,mutationsofTCF-4arerarewith315August10,2011|Volume2|Issue8|WJCO|www.
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comTable2AberrantexpressionofWnt/β-cateninpathwaycom-ponentsinlivercancerComponentExpressionintumourtissuesvsnon-tumour/healthytissuesIncidence(%)MethodRef.
β-cateninHigh40-70IHC[40-43]Wnt1High41PCR[69]Wnt3High39-76PCR[70,71]Wnt4High20PCR[71]Wnt5AHigh25PCR[71]FZD3High41PCR[71]FZD6High31PCR[71]FZD7High33-90PCR[70-72]phospho-GSK3βHigh52IHC[73]Axin1Low67IHC[76]DvlHigh71Westernblotting[82]Prickle-1Low55PCR[82]HDPR1Low58PCR[83]PIN1High53Westernblotting[65]TCF-4High91PCR[87]LEF-1High52IHC[88]CDH17High72IHC[90]CDH17:Cadherin-17;Dvl:Dishevelled;FZD:Frizzled;phospho-GSK3β:Phosphorylatedglycogensynthasekinase3β;HDPR1:HumanhomologueofDapper;IHC:Immunohistochemistry;LEF:Lymphoidenhancerfactor;PCR:Polymerasechainreaction;PIN1:Peptidyl-prolylcis/transisomerase;TCF:T-cellfactor.
FatimaSetal.
DKKsandWnt/β-cateninsignallingJiangetal[87]reportingmutationsin2of32HCCcases,whereasCuietal[25]didnotreportanymutationin34HCCcases.
However,overexpressionofTCF-4inHCCtissueshasbeencorrelatedtoc-Mycoverexpression,tu-mourcapsulestatusandintrahepaticmetastasis[87].
LEF-1isalsooverexpressedinHCCandassociatedwithcyclinD1overexpression,butitisnotfoundtobecorrelatedwithanyclinicopathologicalparameters[88].
Therefore,itisnotknownwhethertheaberrantexpressionofTCF-4andLEF-1isaprimaryeventinHCCoraresultofab-errantWnt/β-cateninsignallinginHCC.
ExpressionofotherTCF/LEFfamilymembersinHCChasnotbeenreported.
Cadherin-17Cadherin-17(CDH17)belongstothecadherinsuperfam-ilycomprisingtransmembraneglycoproteinsthatmediatecalcium-dependentcell-celladhesion[89].
Sinceβ-cateninplaysanessentialroleincadherin-mediatedcell-celladhe-sionaswellasinWnt/β-cateninsignalling,ourlaboratoryidentifiedCDH17toaffectWnt/β-cateninsignallinginHCC.
CDH17isoverexpressedinHCCcellsandinmorethan70%ofHCCcases[90].
Inaddition,overexpressionofanalternativesplicevariantofCDH17(lackingexon7)inmorethan50%ofHCCiscorrelatedtotumourrecur-rence,venousinfiltrationandreducedoverallsurvival[91].
Interestingly,theCDH17splicevariantisfoundtobetriggeredbytwosinglenucleotidepolymorphismsthatareidentifiedasgeneticfactorscontributingtothehighdevel-opmentofHCCinAsia[92].
Furthermore,RNAinterfer-ence(RNAi)-mediatedknockdownofCDH17inmeta-staticHCCcellshasbeenshowntoinhibittumourigenesisinvivoandreduceWnt/β-cateninsignallingbydecreasingphospho-GSK3βandcyclinD1.
Thiswasaccompaniedbyre-localisationofβ-catenintothecytoplasm[93].
TetraspaninsTetraspaninsaretransmembraneproteinsknowntoaf-fectawiderangeoffunctionsincludingcell-celladhe-sion,cellgrowthandsuppressionofmetastasis[94].
TherecentinvolvementoftetraspaninsCD9andCD82inanovelmechanismtoantagonizeWnt/β-cateninsignallingbyexosomalreleaseofβ-cateninisanexcitingavenuetoexploreinHCC.
Thisexosomalreleaseofβ-cateninmaybecompromisedincancerswithhighWnt/β-cateninsignalling.
CD9andCD82aresuppressorsofmetastasisandtheirexpressionisreducedinHCCwithportalveininvasionand/orintrahepaticmetastasis[95].
Chairoungduaetal[38]demonstratedWnt/β-cateninsignallinginhibitioninametastaticcelllinefollowingrestorationofCD82expression.
Thus,thesetetraspaninsmaysuppressmetas-tasisbyantagonizingWnt/β-cateninsignallingbytarget-ingβ-cateninforexosomalrelease.
ItwillbeimportanttoinvestigatethecorrelationbetweenCD9andCD82withβ-catenininHCC.
MicroRNAsMicroRNAs(miRNAs)aresmallnon-codingRNAsthatregulatepost-transcriptionalgeneexpression[96].
TheyareaberrantlyexpressedinHCCcomparedtotheirnon-tumourlivertissues[97-99]andcontributetolivertumou-rigenesis[100,101].
SeveralmiRNAshavebeenidentifiedtoaffecttheWnt/β-cateninpathway[102].
Usingaglobalmicroarray-basedmiRNAprofilingapproach,Jietal[103]identifiedmiRNA-181(miR-181)tobeupregulatedinHCCtumoursthatwerepositiveforepithelialcelladhe-sionmolecule(EpCAM)andAFP(EpCAM+AFP+).
SuchtumoursdemonstratedcancerstemcellpropertiesandanactivationofWnt/β-cateninsignalling.
InvitrostudiesshowedacorrelationbetweenoverexpressionofmiR-181andβ-catenininHCCcellsandfurtherdemonstratedthatmiR-181promotedthestemnessofEpCAM+AFP+HCCcellsbytargetingCDX2(caudaltypehomeoboxtranscriptionfactor2),GATA6(GATAbindingprotein6,ahepatictranscriptionalregulatorofdifferentiation)andnemo-likekinase(NLK,aninhibitorofWnt/β-cateninsignalling).
ThesefindingsprovideevidencethatmiR-181istranscriptionallyactivatedbyWnt/β-cateninsignallingandinturninhibitsitsregulators.
Inaddition,miR-375isanothermiRNAinvolvedintheWnt/β-cateninpathwayanditisdownregulatedbyβ-catenininHCC[104].
How-ever,thefunctionofmiR-375andthemechanismsbywhichitisregulatedbyβ-cateninarenotclear.
FurtherresearchisneededtoinvestigatetheinvolvementofmiR-NAsinWnt/β-cateninsignallinginHCC.
Yes-associatedproteinTheHipposignallingpathwaycontrolsorgansizebyregulatingcellproliferationandapoptosis.
Thesignallingcascadeofthispathwayultimatelyleadstothephosphor-ylationofyes-associatedprotein(YAP),adownstreameffectorofthispathway.
YAPisatranscriptionalco-ac-tivatoranditsphosphorylationcausesittoremaininthecytoplasmandpreventthetranscriptionofgenesrespon-sibleforcellproliferationandinhibitionofapoptosis[105].
Recently,afewstudieshavedescribedtheHippopathwayasanegativeregulatorofWnt/β-cateninsignalling[106,107].
Varelasetal[106]reportedphosphorylatedTaz(componentoftheHippopathway)toinhibittheactivationofDvl,therebypreventingβ-cateninstabilisationandactivation.
Heallenetal[107]recentlyshowednuclearinteractionofunphosphorylatedYAPandβ-cateninincardiaccellsofmicewithdysregulatedHipposignalling.
ThesemicehadenlargedheartsandoverexpressedWnt/β-catenintargetgenes.
Additionally,dysregulationoftheHipposignallingpathwayandinhibitionofβ-cateninresultedinrestric-tionofcardiomyocyteovergrowth.
Thisstudyofferedinsightsintothedirectinteractionbetweenthedown-streameffectorsofthesetwoimportantpathways.
InHCC,nuclearoverexpressionofYAP(unphosphorylatedYAP)hasbeenreportedin62%ofHCCandhasbeenassociatedwithshortdisease-freesurvivalandoverallsurvival[108].
Sinceβ-cateninisalsofoundtoaccumulateinthenucleusofHCCpatients[43,45],furtherstudiesarewarrantedtounderstandtheclinicalimplicationsofYAPandβ-cateninoverexpressioninHCC.
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comFatimaSetal.
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comWNTSIGNALLINGANTAGONISTSAsmentionedabove,therearemanyfactorsaffectingtheWnt/β-cateninpathwayinHCC.
However,theoccur-renceofthesefactorsisnotabsoluteineachclinicalcaseofHCC.
Therefore,theinvolvementofotherfactorsinmodulatingtheWnt/β-cateninpathwayisspeculated.
FactorsupstreamofGSK3β/Axin/APCproteincom-plex,likethoseoccurringattheextracellularlevel,mayalsobethoseinvolved.
Forthis,secretedWntantagonistsaredistinguishedexamples.
TheseantagonistscanbedividedbroadlyintotwogroupsbasedontheirdifferentmechanismsinpreventingtheinteractionofWntwithLRP5/LRP6[109].
GroupⅠconsistsofWise,sclerostinanddickkopfs(DKKs)thatbinddirectlytoLRP5/LRP6.
GroupⅡcomprisesWntinhibitoryfactorandsecretedfrizzled-relatedproteinthatactbydirectlybindingtoWntproteinsandpreventtheformationoftheWntreceptorcomplex.
ThisreviewwillfocusontheroleofDKKsontheWnt/β-cateninpathwayinHCC.
StructureofDKKsTheDKKfamilyconsistsoffourmembers(DKK1toDKK4).
Theyaresecretedglycoproteinsof225-350ami-noacidswithmolecularweightsbetween25and29kDaforDKK1,DKK2andDKK4,and38kDaforDKK3.
DKKscontaintwoconservedcysteine-richdomains,eachofwhichisseparatedbyalinkerregionofvariouslengths[110].
Eachcysteine-richdomaincontainstencys-teineresidues.
Theamino-terminalcysteine-richdomain(Cys-1)isuniquetoeachDKK,whereasthecarboxyl-terminalcysteine-richdomain(Cys-2)ishighlyconservedamongallmembersoftheDKKfamily.
ThepositionofeachcysteineresidueintheCys-2domaincloselyre-semblesproteinsinthecolipasefamily[111].
Becauseoftheroleofcolipasesinlipidhydrolysis[112],thepresenceofthisfeaturesuggeststheabilityofDKKstointeractwithlipidsinregulatingWnt/β-cateninsignalling[111].
AmongallDKKs,DKK3isthemostdivergentmember[113].
Itcontainsanextendedamino-terminaldomainprecedingtheCys-1regionandanextendedcarboxyl-terminaldo-mainfollowingtheCys-2domain.
AllDKKspossesssev-eralpotentialsitesforproteolyticcleavagebyfurin-typeproteases,indicatingthattheymaybesubjectedtopost-translationalmodifications[114].
Figure2AandBillustratethedifferencesbetweendifferentDKKs.
FunctionsofDKKsontheWnt/β-cateninpathwayMembersoftheDKKfamilydiffernotonlyintheirstructuresbutalsointheirmRNAexpressioninHCCandintheirabilitytomodulateWnt/β-cateninsignalling.
Table3summarizesthesedifferencesbetweenmembersoftheDKKfamily.
DKK1isthemoststudiedmemberoftheDKKfamily.
ItwasoriginallyidentifiedasaheadinducerwhenitsmRNAwasinjectedintoXenopusembryos[115].
Experi-mentsinactivatingXenopusDKK1withanti-DKK1anti-bodies[115]andinvolvingDKK1knockoutmice[116]showalackofanteriorheadstructures,highlightingitsimpor-tanceinheadformation.
DKK1inhibitsWnt-inducedstabilisationofβ-cateninandtwomodelshavebeenpro-posed.
ThefirstmodelproposesthatDKK1bindstotheextracellulardomainofLRP5/LRP6andpreventstheformationoftheFZD-Wnt-LRP5/LRP6complexinre-sponsetoWnt,therebyattenuatingWntactivity[117].
ThesecondmodelproposesthatDKK1inhibitsWntsignal-lingbyinducingclathrin-dependentinternalisationofLRP6[37].
However,contrarytotheresultsofYamamotoetal[37],Blitzeretal[118]usedmousefibroblastcellstoshowthatclathrin-dependentinternalisationofLRP6isrequiredtopropagateWnt/β-cateninsignalling,anddisturbingthisclathrin-mediatedendocytosisblocksWntactivity.
TheserecentfindingssuggestthatmechanismsofDKK1an-tagonisticactivitymayvaryindifferentcelltypes.
Figure2Domainstructureandphylogenetictreeofhumandickkopfproteins.
A:Eachdickkopf(DKK)containstwocysteine-richdomains,eachofwhichisseparatedbyalinkerregionofvariouslengths.
Theamino-terminalcysteine-richdomain(Cys-1)domainsareuniquetoeachDKK,whereasthecarboxyl-terminalcysteine-richdomain(Cys-2)domainsareconservedamongallmembersoftheDKKfamily;B:PhylogenetictreeoftheDKKproteins.
AminoacidsequenceswerealignedbytheClustalWprogram,andthephylogenetictreewasconstructedbytheneighbourjoiningmethod.
Thescalebarindicatestheestimatednumberofsub-stitutionsper50aminoacids.
SP:Signalpeptide.
DKK30.
05DKK4DKK2DKK1DKK1DKK2DKK3DKK4266aminoacids259aminoacids350aminoacids224aminoacidsScalebar50aminoacidsBALinkerregionSPSPSPSPCys-1Cys-1Cys-1Cys-1Cys-2Cys-2Cys-2Cys-2FatimaSetal.
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comInadditiontobindingtoLRP5/LRP6,DKK1alsobindstoKremen1(Krm1)andKrm2,whichbelongtoanotherclassoftransmembranereceptors[119,120].
DKK1bindstoKrm1andKrm2withhighaffinityandthisinhibitsWnt/β-cateninsignalling[121].
Despitethat,geneknockoutstudiesinmicehaveshownthatKrm1andKrm2arenotuniversallyrequiredforDKK1-associatedfunction[122].
ItwasdemonstratedthatDKK1mutantsareabletoantagonizeWntactivitywithoutbindingtoKrm1orKrm2[123].
Therefore,KrmsmaynotbeessentialforDKK1functionandfurtherstudiesareneededtounder-standtheirinvolvementinWnt/β-cateninsignalling.
AmongallDKKs,DKK4demonstratessimilaran-tagonisticactivitytowardstheWnt/β-cateninpathwayasDKK1bybindingtoLRP5/LRP6andKrms[120].
WhilefunctioningupstreamoftheWnt/β-cateninpathway,DKK1andDKK4arealsodownstreamtargetsoftheWnt/β-cateninpathway,creatinganegativefeedbacklooptoregulateWnt/β-cateninsignalling[124,125].
However,thisfeedbackmechanismisoftenabrogatedincancersincludingHCC[125,126].
LikeDKK1andDKK4,DKK2alsobindstoLRP5/LRP6andKrms.
However,DKK2mayserveasanan-tagonistoranagonisttotheWnt/β-cateninpathwaydependingoncellularcontext.
Forinstance,overexpres-sionofDKK2in293fibroblastcellsresultsinWnt/β-cateninpathwayactivation,whereasco-transfectionofDKK2andKrm2inthesamecelltypeinhibitsthispathway[127].
Toexplainthisphenomenon,Chenetal[128]identifiedYWTDβ-propellerdomainsofLRP5/LRP6asthedockingsitesforCys-2ofmouseDKK2,whilethisCys-2domainalsocontainsbindingsiteforKrm1andKrm2.
Therefore,theexpressionofKrmsservesasaswitchforthedualroleofDKK2ontheWnt/β-cateninpathway.
UnlikeotherDKKshavingaroleinWnt/β-cateninsignallingbybindingtoLRP5/LRP6andKrms,thereceptorforDKK3hasnotbeenidentifiedanditsef-fectonthispathwayremainsunclear.
EarlierstudiesinXenopussuggestedthatDKK3isnotinvolvedinWnt/β-cateninsignalling[113,115],butrecentstudieshavedemon-stratedthatDKK3isassociatedwithareductionincyto-plasmicandnuclearaccumulationofβ-catenininSaos-2osteosarcomacells,lungcancercellsandcervicalcancercells[129-131].
Interestingly,Leeetal[130]identifiedβ-TrCPasabindingpartnertoDKK3,andpossiblyDKK3mayreduceβ-cateninlevelsviaubiquitination.
Therefore,thepotentialroleofDKK3inWnt/β-cateninpathwayre-mainstobedetermined.
SincedifferentDKKsexhibitdifferenteffectsonWnt/β-cateninactivity,itwillbeimportanttostudythemechanismsbywhicheachmemberoftheDKKfamilyexertsitseffectontheWnt/β-cateninpathway.
Further-more,asreportedbyYamamotoetal[37]andBlitzeretal[118],DKKsmayhavedifferentmechanismsofactionindif-ferentcelltypes.
Additionally,sharingthesamereceptormaynotimplyexhibitingthesameeffectasinthecaseofDKK1andDKK2.
Forinstance,theybothbindtoLRP5/LRP6andKrms,butDKK1servesasanantago-nist,whereasDKK2servesasbothanagonistandanantagonisttotheWnt/β-cateninpathway.
DKKsinHCCAsmentionedabove,theWnt/β-cateninpathwayplaysacriticalroleinHCCandnotsurprisingly,Wntinhibitors,includingDKKs,areinvolved.
MoreresearchstudieshavebeendedicatedtostudyingtheroleofDKKsinHCCoverthepastfewyears.
DKK1SeveralstudieshavereportedoverexpressionofDKK1inHCCcelllinesandtissues[126,132,133],whileYuetal[126]wasthefirsttodemonstrateacorrelationbetweenDKK1overexpressionandcytoplasmic/nuclearβ-cateninaccu-mulationinHCC.
Itwasdemonstratedthroughinvitroas-saysthatDKK1failedtoinhibitTCF-mediatedtranscrip-tionalactivityinHCCcellswithcytoplasmicornuclearβ-cateninaccumulation,suggestinganabrogationofthenegativefeedbackloopofDKK1inHCC.
SurvivalanalysiscorrelatedoverexpressionofDKK1withpoorprognosisofHCCpatients,andDKK1wasidentifiedasanindependentprognosticmarkerforoverallsurvivalandCys-1:Amino-terminalcysteine-richdomain;Cys-2:Carboxyl-terminalcysteine-richdomain;HCC:Hepatocellularcarcinoma;LRP:Lipoproteinreceptor-relatedprotein;DKK:Dickkopf.
Table3DifferencesbetweentheDKKfamilymembersPropertyDKK1DKK2DKK3DKK4Ref.
VariantsUnknownUnknown2Unknown[130]LocationofCys-185-138aminoacids78-127aminoacids147-195aminoacids41-90aminoacids[110]LocationofCys-2189-263aminoacids183-256aminoacids208-284aminoacids145-218aminoacids[110]Lengthoflinkerregion(numberofaminoacids)50561254[110]ReceptorLRP5/LRP6LRP5/LRP6NotidentifiedLRP5/LRP6[113]ActivityinWnt/β-cateninsignallinginHCCAntagonistNotreportedNotreportedNotreported[126]ExpressioninHCCtissuesOverexpressedReducedReducedNotreported[126,143]PhenotypeofknockoutmiceEmbryoniclethalityViable,fertile,blindness,osteopaeniaViable,fertile,hyperactive,increasedIgM,naturalkillercellsandhaematocritlevelsNotreported[116,162-164]FatimaSetal.
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comdisease-freesurvival.
The5-yearoverallsurvivalanddis-ease-freesurvivalratesforHCCpatientsoverexpressingDKK1(43.
4%and34.
2%,respectively)weresignificantlylowerthanHCCpatientswithreducedDKK1expres-sion(59.
3%and55.
2%,respectively).
AlthoughelevatedlevelsofAFPremainthegoldstandardforscreeningHCC,thereare,however,asubgroupofpatientswhohaveHCCandnormallevelsofAFP.
WhenpatientswerestratifiedaccordingtoAFPlevels,DKK1overexpressiondemonstratedworseprognosisforAFP-normalHCCpatients,suggestingthatDKK1mayserveasaprognosticmarkerforthisgroupofpatients.
Furthermore,HCCpatientswithhighDKK1andβ-cateninexpressionalsoshowedpoorprognosis.
The5-yearoverallsurvivalanddisease-freesurvivalrateswere66.
0%and59.
8%,respec-tively,forHCCpatientswithoutDKK1andβ-cateninexpression,and46.
0%and18.
0%forHCCpatientswithhighDKK1andhighβ-cateninexpression[126].
ThisstudyhighlightstheimportantroleofDKK1inWnt/β-cateninsignallinginHCC.
OtherthantotalAFPlevels,lensculinarisagglutinin–reactiveAFP(AFP-L3)andprothrombininducedbyvitaminKabsence-Ⅱ(PIVKA-Ⅱ)havebeenreportedastumourmarkersforHCC.
HighserumAFP-L3levelshaverecentlybeenreportedasaprognosticmarkereveninHCCpatientswithlowAFPlevels[134].
Additionally,highserumlevelsofPIVKA-ⅡhavebeenassociatedwithadvancedHCCwithportalveininvasion[135].
BecauseofitshighexpressioninHCCtissuesanditssecretorynature,DKK1ishypothesizedtobepresentathighlevelsintheserumofHCCpatients.
However,therearenostudiesevaluatinghighDKK1serumlevelsonHCCprogressionorprognosisanditwouldbeim-portanttoconductsuchastudytounderstandtheclinicalsignificanceofDKK1inHCC.
Ontheotherhand,highlevelsofDKK1inpatients'serumareassociatedwithpoorprognosisinvariouscancersincludingoesophagealsquamouscellcarcinoma[136],lungcancer[137],breastcan-cer[138]andcervicalcancer[138],suggestingthattheserumlevelofDKK1mayalsoreflecttheprognosisofHCCpatients.
Inmultiplemyeloma,highDKK1serumlevelsareassociatedwithosteolyticbonelesions[139]andpatientsrespondingtoanti-myelomatreatmentshowadecreaseinDKK1serumlevels[140],suggestingtheinvolvementofDKK1inthisaspect.
Recently,Fulcinitietal[141]evaluatedtheeffectofanti-DKK1monoclonalantibody(BHQ880)inamultiplemyelomamousemodelandfoundthatitinducedboneformationandinhibitedtumour-inducedosteolyticbonelesions.
Likemultiplemyeloma,HCCisalsoosteolyticinnaturewith20%ofHCCpatientshav-ingbonemetastasis[142],makingitimportanttoassesstheroleofDKK1inbonemetastasisinHCC.
DKK2InHCC,ahigherlevelofDKK2methylationwasde-tectedinHCCtissuescomparedtocorrespondingnon-cancerouscirrhotictissues[143],suggestingitsroleinhepatocarcinogenesis.
EpigeneticsilencingofDKK2hasalsobeenreportedingastriccancer[144],oesophagealsquamouscellcarcinoma[145]andrenalcellcarcinoma[146].
Inrenalcellcarcinoma,nosignificantrelationshipwasfoundbetweenDKK2methylationandβ-cateninexpres-sion[146].
AlthoughtheeffectofDKK2onWnt/β-cateninsignallingdependsontheexpressionofLRP5/LRP6andKrms,DKK2expressionhasnotbeenstudiedinthecontextofthesemolecules.
Furthermore,therearecurrentlynoreportsontheeffectofDKK2onWnt/β-cateninsignallinginHCC.
DKK3TherearefewreportsontheclinicalsignificanceofDKK3inHCC[143,147].
ReductioninDKK3expressionisassociatedwithincreasedfrequencyofmethylationinHCCtissuescomparedtocorrespondingnon-cancerouscirrhotictissues,implyingthatDKK3methylationmaynotbeanearlyeventinHCC,butmayfunctionintheprogressionofHCC.
Furthermore,DKK3methylationhasbeensignificantlyassociatedwithshortprogression-freesurvivalinHCCpatients[143].
TheeffectofDKK3onWnt/β-cateninsignallinghasnotbeenreportedinHCC,butreducedDKK3expressionhasbeenshowntocorrelatewithβ-cateninaccumulationinlungcancer[131].
AlthoughtherearenoreportsofDKK3levelinHCCserum,reducedDKK3serumlevelsinovariancancerareassociatedwiththepresenceoflymphnodemetastasis,andhighDKK3serumlevelshavebeenassociatedwithlargetumoursincervicalcancer[148].
Interestingly,mul-tigenemethylationstatusofacombinationofWntan-tagonistgenes,includingDKK3andothers,intheserumhavebeenproposedasmarkersfordiagnosis,stagingandprognosisofrenalcellcarcinoma[149].
AlthoughdifferentWntantagonistsmayfunctiondifferently,theircumula-tivesilencingmayserveasamolecularmarkerforcancerdetection.
DKK4DKK4isleaststudiedincancer.
Itislocatedonchromo-some8p11.
2-p11.
1andthischromosomalregionexperi-encesfrequentlossofheterozygosityinHCC[150].
ThismayexplainreducedexpressionofDKK4inHCCcelllineswithoutdetectionofDKK4methylation[144].
Cur-rentlytherearenoreportsonDKK4expressioninHCCtissuesoritseffectonWnt/β-cateninsignallinginHCC.
Recently,Hirataetal[151]reportedareductionofWnttargetgenesafterectopicexpressionofDKK4inrenalcarcinoma-derivedCakicells.
However,overexpressionofDKK4alsoresultedinactivationoftheJNKpathwayandenhancedtumourgrowthinvivo.
ThissuggeststhatDKK4maybeinvolvedinpathwaysotherthanWnt/β-cateninsignalling.
POTENTIALTHERAPEUTICTARGETSFORWNT/β-CATENINSIGNALLINGINHCCMountingevidencesuggeststheroleofβ-cateninstabi-FatimaSetal.
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comlisationinpromotingtumourproliferationinHCCpa-tients[43,152].
SuchobservationsmakeWnt/β-cateninsig-nallinganattractivetargetforcancertherapy.
Inlinewiththishypothesis,smallmoleculeinhibitorshavebeende-velopedtohinderWnt/β-cateninsignallingbydisruptingprotein-proteininteractionsofcomponentsofthispath-way.
Theseincludethefungalderivatives,PKF115-584andCGP049090,thatfunctiontoimpedetheinteractionbetweenβ-cateninandtheTCFcomplex[153].
Emamietal[154]reportedanothermoleculecalledICG-001,whichdisruptstheinteractionbetweenβ-cateninandCBP.
Morerecently,pyrviniumpamoate,ananthelminticdrug,wasshowntoinhibittheWnt/β-cateninpathwaybyallo-stericactivationofCKIαandsubsequentlyincreasedlev-elsofβ-catenindestructioncomplexsecondarytoAxinstabilisation[155].
TherapeuticantibodiesagainstWnt1andWnt2havealsodemonstratedWnt/β-cateninsignallinginhibitionandsuppressionoftumourgrowthinvivo[156,157].
β-cateninsuppressionthroughchemoprophylaxismayofferanotheralternativetherapy.
R-Etodolac(enantiomerofthenon-steroidalanti-inflammatorydrugEtodolac)reducedproliferationandsurvivaloftwoHCCcelllines(HepG2andHep3B)bydecreasingthetotalandactiveforms(dephosphorylatedatSer33/Ser37/Thr41)ofβ-catenin[158].
FurtherstudieswillbeimportanttoaccessclinicalimplicationsofthesepotentialtargetsinHCC.
PERSPECTIVESAberrantactivationofWnt/β-cateninsignallingisanimportanteventinHCCthatleadstotranscriptionofvarioustargetgenesinvolvedincarcinogenesis.
ItwillbeclinicallyrelevanttotargettheWnt/β-cateninpathwayandregulateitsactivity.
However,sincethepathwaycanbeaberrantlyactivatedbythedysfunctionofseveralgenes,itisimportanttoensurethatwhenonememberistargetedtheotherfunctionsofthesametarget,ifany,arenotdisrupted.
Forinstance,β-cateninisinvolvedintheWnt/β-cateninpathwayandplaysacriticalroleincell-celladhesion.
Therefore,careshouldbetakenindesigningreagentsfordisruptionofmoleculeswithdualfunctions.
Fortumourswithmutatedβ-catenin,oneapproachcouldbetoutilizeRNAitargetingmutantβ-cateninfortherapy,asthiswilltargetselectivelyfortumourcells,butnothealthycells.
However,mutantβ-catenin-negativetumourswithaberrantWnt/β-cateninsignallingofferthegreatestchallengeastherecouldbeamultitudeofreasonsforaberrantWnt/β-cateninactiva-tion.
Therefore,alteringWnt/β-cateninsignallingmaybeadvantageousfortherapeuticmeansbutthereareca-veatsandlimitationsinvolved.
Inlinewiththeseinvestigations,DKKshavebeendiscoveredoverthepast12yearsfortheirabilitiestoin-terfereintheWnt/β-cateninpathway.
Sincethen,muchefforthasbeendedicatedtoexploringtheirfunctionsandimplicationsinliverdevelopmentanddisease.
Dif-ferentDKKsexhibitdifferentexpressionsandfunctionsinvariouscancers.
Someimportantquestionsremaintobeanswered.
Forexample,whereareDKKslocalisedinHCCcellsIstheirexpressionassociatedwithcytoplas-mic/nuclearβ-cateninaccumulationinHCCcellsDoDKKshaveprognosticvalueinHCCpatientsDotheyexerttheireffectsonbothwildtypeandmutantβ-catenininHCCcellsDoDKKsdegradeβ-cateninviaaubiq-uitination-dependentmechanismAredifferentDKKsinvolvedindifferentstagesofHCCdevelopmentWhatisthereceptorforDKK3AreDKKsredundantintheirfunctionsFurthermore,thenegativefeedbackmecha-nismofDKK1alsowarrantsfurtherresearch.
AlthoughDKK1inhibitsWnt/β-cateninsignalling,itsoverexpres-sionhasnoeffectonHCCcellswithcytoplasmic/nuclearβ-cateninaccumulation[126].
ThismaybesuggestiveofanabrogatednegativefeedbacklooporitmayalsoimplythattheinhibitoryeffectofDKK1isonlyfunctionalun-tilreachingapointofsaturationbeyondwhichitcannotexertitsinhibitoryeffect.
Insummary,comparedtotheoverwhelmingbodyofevidenceshowingthefunctionalroleofWnt/β-cateninsignallinginHCC,thebiologicalandphysiologicalrolesofDKKsinrelationtothispath-wayremaintobediscovered.
DKKsprovideanewav-enuetoexploreandtheyaddanotherlevelofcomplexitytothealreadycomplexWnt/β-cateninsignallinginHCC.
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