title: Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21.
abstract: The mechanisms linking immune responses and inflammation with tumor development are not well understood. Here, we show that the soluble form of the extracellular matrix proteoglycan decorin controls inflammation and tumor growth through PDCD4 (programmed cell death 4) and miR-21 (microRNA-21) by two mechanisms. First, decorin acted as an endogenous ligand of Toll-like receptors 2 and 4 and stimulated production of proinflammatory molecules, including PDCD4, in macrophages. Second, decorin prevented translational repression of PDCD4 by decreasing the activity of transforming growth factor-β1 and the abundance of oncogenic miR-21, a translational inhibitor of PDCD4. Moreover, increased PDCD4 abundance led to decreased release of the anti-inflammatory cytokine interleukin-10, thereby making the cytokine profile more proinflammatory. This pathway operates in both pathogen-mediated and sterile inflammation, as shown here for sepsis and growth retardation of established tumor xenografts, respectively. Decorin was an early response gene evoked by septic inflammation, and protein concentrations of decorin were increased in the plasma of septic patients and mice. In cancer, decorin reduced the abundance of anti-inflammatory molecules and increased that of proinflammatory molecules, thereby shifting the immune response to a proinflammatory state associated with reduced tumor growth. Thus, by stimulating proinflammatory PDCD4 and decreasing the abundance of miR-21, decorin signaling boosts inflammatory activity in sepsis and suppresses tumor growth.
authors.affiliation: 1Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Rosetta
authors.initials: R
authors.lastname: Merline
authors.forename: Kristin
authors.initials: K
authors.lastname: Moreth
authors.forename: Janet
authors.initials: J
authors.lastname: Beckmann
authors.forename: Madalina V
authors.initials: MV
authors.lastname: Nastase
authors.forename: Jinyang
authors.initials: J
authors.lastname: Zeng-Brouwers
authors.forename: José Guilherme
authors.initials: JG
authors.lastname: Tralhão
authors.forename: Patricia
authors.initials: P
authors.lastname: Lemarchand
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schaefer
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D058575:Decorin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D051017:Apoptosis Regulatory Proteins; C546879:Dcn protein, mouse; D058575:Decorin; C556062:IL10 protein, mouse; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10
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