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Sci. Signal., 15 November 2011
Vol. 4, Issue 199, p. ra75
[DOI: 10.1126/scisignal.2001868]

RESEARCH ARTICLES

Signaling by the Matrix Proteoglycan Decorin Controls Inflammation and Cancer Through PDCD4 and MicroRNA-21

Rosetta Merline1, Kristin Moreth1, Janet Beckmann1, Madalina V. Nastase1, Jinyang Zeng-Brouwers1, José Guilherme Tralhão2, Patricia Lemarchand3, Josef Pfeilschifter1, Roland M. Schaefer4, Renato V. Iozzo5*, and Liliana Schaefer1*{dagger}

1 Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
2 Department of Surgery, Surgery 3, Coimbra University Hospital, 3000-075 Coimbra, Portugal.
3 Inserm, UMR915, Université de Nantes, CHU de Nantes, l’Institut du thorax, 44000 Nantes, France.
4 Department of Medicine D, University Hospital of Muenster, 48149 Muenster, Germany.
5 Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107 USA.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: schaefer{at}med.uni-frankfurt.de

Citation: R. Merline, K. Moreth, J. Beckmann, M. V. Nastase, J. Zeng-Brouwers, J. G. Tralhão, P. Lemarchand, J. Pfeilschifter, R. M. Schaefer, R. V. Iozzo, L. Schaefer, Signaling by the Matrix Proteoglycan Decorin Controls Inflammation and Cancer Through PDCD4 and MicroRNA-21. Sci. Signal. 4, ra75 (2011).

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