Clusterin induces matrix metalloproteinase‐9 expression via ERK1/2 and PI3K/Akt/NF‐κB pathways in monocytes/macrophages

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: MMP‐;    9;    glycosylation;    ECM remodeling;    tumor invasion;    inflammation;   

DOI  :  10.1189/jlb.0311110

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Mostsolidtumortissuespossessasignificantpopulationofmacrophages,whichareknowntobecloselylinkedwithtumorprogressionandmetastasis.Clusterinhasbeenreportedtobeoverexpressedinvarioustumorsandtohaveatumor‐promotingrole.Asclusterininductionandmacrophageinfiltrationoccurconcurrentlyatthetumorsite,itraisesapossibilitythatclusterinmayregulatethefunctionofmacrophagesviafacilitatingECMremodeling.Here,wedemonstrateforthefirsttimetheexpressionofMMP‐9byclusterininhumanprimarymonocytesaswellashumanandmurinemacrophagecelllines,THP‐1,andRaw264.7.MMP‐9expressionwasaccompaniedbyincreasedenzymaticactivity,asrevealedbygelatinzymography.TheMMP‐9activitypromotedbyclusterinwasfoundtobedependentontheactivationofERK1/2andPI3K/Aktbutnotp38orJNKpathways.InhibitionofPI3KactivitydidnotaffecttheactivationofERK1/2andviceversa,indicatingthatthetwopathwayswereindependentlyoperatedtostimulateMMP‐9activity.Moreover,clusterinfacilitatednucleartranslocationofNF‐κBp65alongwithIκB‐αdegradationandphosphorylation,whichwascriticalforMMP‐9expression.AsNF‐κBisacentralregulatorofinflammation,clusterinmayprovideamolecularlinkbetweeninflammationandcancerviaup‐regulatingNF‐κBandMMP‐9.Collectively,thesedatahighlightanovelroleofclusterinasastimulatorforMMP‐9expressioninmacrophages,whichmaycontributetothetissuereorganizationbyservingasamodulatorforECMdegradation...

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