title: Placental growth factor-1 and -2 induce hyperplasia and invasiveness of primary rheumatoid synoviocytes.
abstract: 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.
authors.affiliation: Pohang University of Science and Technology-Catholic Biomedical Engineering Institute, Catholic University of Korea, Seoul 137-701 Korea;
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.affiliation: Department of Chemical Engineering, Pohang University of Science and Technology, Pohang 790-784, Korea;
authors.forename: Ji-Hwan
authors.initials: JH
authors.lastname: Park
authors.affiliation: Pohang University of Science and Technology-Catholic Biomedical Engineering Institute, Catholic University of Korea, Seoul 137-701 Korea;
authors.forename: Seong-Hye
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Pohang University of Science and Technology-Catholic Biomedical Engineering Institute, Catholic University of Korea, Seoul 137-701 Korea;
authors.forename: Sang-Min
authors.initials: SM
authors.lastname: Oh
authors.affiliation: Pohang University of Science and Technology-Catholic Biomedical Engineering Institute, Catholic University of Korea, Seoul 137-701 Korea;
authors.forename: Saseong
authors.initials: S
authors.lastname: Lee
authors.affiliation: Istituto di Genetica e Biofisica Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, 20099 Milan, Italy;
authors.forename: Valeria
authors.initials: V
authors.lastname: Cicatiello
authors.affiliation: Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu 711-873 Korea;
authors.forename: Sangchul
authors.initials: S
authors.lastname: Rho
authors.affiliation: Istituto di Genetica e Biofisica Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; Bio-Ker, MultiMedica Group, 80131 Naples, Italy;
authors.forename: Sandro
authors.initials: S
authors.lastname: De Falco
authors.affiliation: Bio-Ker, MultiMedica Group, 80131 Naples, Italy; School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Korea; and.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Pohang University of Science and Technology-Catholic Biomedical Engineering Institute, Catholic University of Korea, Seoul 137-701 Korea; Division of Rheumatology, Department of Internal Medicine, Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.affiliation: Pohang University of Science and Technology-Catholic Biomedical Engineering Institute, Catholic University of Korea, Seoul 137-701 Korea; Division of Rheumatology, Department of Internal Medicine, Catholic University of Korea, Seoul 137-701, Korea wan725@catholic.ac.kr.
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D061251:Primary Cell Culture; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1