Overexpression of progelatinase B/proMMP‐9 affects migration regulatory pathways and impairs chronic lymphocytic leukemia cell homing to bone marrow and spleen

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

关键词: CLL;    RhoA;    PTEN;    lymphoid organs;   

DOI  :  10.1189/jlb.3HI0913-521R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Thisstudyaddressestheroleof(pro)MMP‐9overexpressioninCLLcellmigration.WehaveusedprimaryCLLcellsandCLL‐derivedMEC‐1cellstransfectedwithempty(mockcells)orproMMP‐9‐encoding(MMP‐9cells)lentiviralvectors.Theconstitutive(pro)MMP‐9expressioninmockcellsandprimaryCLLcellswassimilar,whereasinMMP‐9cells,expressionresembledthatofCLLcellsincubatedwithproMMP‐9.Inxenograftmodels,inNOD/SCIDmice,MMP‐9‐MEC‐1transfectantsshowedsignificantlyreducedhomingtobonemarrowandspleencomparedwithmockcells.Likewise,incubationofprimaryCLLcellswithproMMP‐9,beforeinjectionintomice,inhibitedtheirhomingtotheseorgans.Thisinhibitionwasspecific,dose‐dependent,andobservedinallCLLtested,independentlyofprognosticmarkersordiseasestage.Additionally,theMMP‐9catalyticactivitywasonlypartiallyinvolved,astheinactivemutantproMMP‐9MutEhadapartialeffect.MMP‐9cellsalsoshowedimpairedmigrationinvitro,whichwasrevertedbyreducing(pro)MMP‐9expressionwithsiRNAs.CLLmigrationthusrequiresoptimal(pro)MMP‐9expressionlevels,beloworabovewhichmigrationishampered.Biochemicalanalysisofthe(pro)MMP‐9effectindicatedthatMMP‐9cellsorprimaryCLLcellsincubatedwithproMMP‐9hadreducedactivationofmigrationregulatorymolecules,includingRhoAGTPase,Akt,ERK,andFAK.Incontrast,p190RhoGAP(RhoAinhibitor)andPTEN(Akt/ERK/FAKinhibitor)wereup‐regulatedinMMP‐9cells.Reductionof(pro)MMP‐9expressionbysiRNAsrestoredRhoAactivityanddiminishedPTENlevels.Ourresultsrevealanovelfunctionfor(pro)MMP‐9inmodulatingsignalingpathwaysleadingtoCLLcellarrest.Therefore,localhigh(pro)MMP‐9expressionmaycontributetomalignantcellretentioninlymphoidorgansanddiseaseprogression...

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