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Placental Growth Factor-1 and -2 Induce Hyperplasia and Invasiveness of Primary Rheumatoid Synoviocytes

Placental Growth Factor-1 and -2 Induce Hyperplasia and Invasiveness of Primary Rheumatoid Synoviocytes
Yoo, SA[Yoo, Seung-Ah]Park, JH[Park, Ji-Hwan]Hwang, SH[Hwang, Seong-Hye]Oh, SM[Oh, Sang-Min]Lee, S[Lee, Saseong]Cicatiello, V[Cicatiello, Valeria]Rho, S[Rho, Sangchul]De Falco, S[De Falco, Sandro]Hwang, D[Hwang, Daehee]Cho, CS[Cho, Chul-Soo]Kim, WU[Kim, Wan-Uk]
DGIST Authors
Rho, S[Rho, Sangchul]
Issue Date
Journal of Immunology, 194(6), 2513-2521
Article Type
AngiogenesisApoptosisArthritis, RheumatoidAutocrine EffectBlotting, WesternCell CultureCell HyperplasiaCell InvasionCell MigrationCell MotionCell MovementCell ProliferationCell SurvivalCell TransformationCells, CulturedConfocal MicroscopyControlled StudyDNA MicroarrayDrug EffectsDrug TargetingFibroblastFibroblast Like SynoviocyteFibroblastsFLT1 Protein, HumanGene ExpressionGene Expression ProfilingGene OverexpressionGene SilencingGenetic TransfectionGeneticsHEK293 Cell LineHEK293 CellsHumanHuman CellHuman TissueHumansHyperplasiaIn Vitro StudyIsoproteinMesenchymeMetabolismMicroscopy, ConfocalMitogen-Activated Protein KinaseNeo-Vascularization (Pathology)Neo-Vascularization, PathologicNeuropilin 1Oligonucleotide Array Sequence AnalysisParacrine SignalingPathologyPhenotypePlacenta ProteinPlacental Growth FactorPlacental Growth Factor 1Placental Growth Factor 2Pregnancy ProteinsPrimary CellPrimary Cell CulturePriority JournalProtein BCL 2Protein ExpressionReceptor BindingReverse Transcriptase-Polymerase Chain ReactionRheumatoid ArthritisRNA InterferenceSmall Interfering RnaSynovial MembraneSynoviocyteSynoviumUnclassified DrugUpregulationVascular Endothelial Growth Factor Receptor-1VascularizationVasculotropin Receptor1Western BlottingXenotransplantation
Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of PlGF transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy. Copyright © 2015 by The American Association of Immunologists, Inc.
American Association of Immunologists
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