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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
- Angiogenesis; Apoptosis; Arthritis, Rheumatoid; Autocrine Effect; Blotting, Western; Cell Culture; Cell Hyperplasia; Cell Invasion; Cell Migration; Cell Motion; Cell Movement; Cell Proliferation; Cell Survival; Cell Transformation; Cells, Cultured; Confocal Microscopy; Controlled Study; DNA Microarray; Drug Effects; Drug Targeting; Fibroblast; Fibroblast Like Synoviocyte; Fibroblasts; FLT1 Protein, Human; Gene Expression; Gene Expression Profiling; Gene Overexpression; Gene Silencing; Genetic Transfection; Genetics; HEK293 Cell Line; HEK293 Cells; Human; Human Cell; Human Tissue; Humans; Hyperplasia; In Vitro Study; Isoprotein; Mesenchyme; Metabolism; Microscopy, Confocal; Mitogen-Activated Protein Kinase; Neo-Vascularization (Pathology); Neo-Vascularization, Pathologic; Neuropilin 1; Oligonucleotide Array Sequence Analysis; Paracrine Signaling; Pathology; Phenotype; Placenta Protein; Placental Growth Factor; Placental Growth Factor 1; Placental Growth Factor 2; Pregnancy Proteins; Primary Cell; Primary Cell Culture; Priority Journal; Protein BCL 2; Protein Expression; Receptor Binding; Reverse Transcriptase-Polymerase Chain Reaction; Rheumatoid Arthritis; RNA Interference; Small Interfering Rna; Synovial Membrane; Synoviocyte; Synovium; Unclassified Drug; Upregulation; Vascular Endothelial Growth Factor Receptor-1; Vascularization; Vasculotropin Receptor1; Western Blotting; Xenotransplantation
- 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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