Publications (5)15.16 Total impact
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Article: Decorin interferes with platelet-derived growth factor receptor signaling in experimental hepatocarcinogenesis.
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ABSTRACT: Decorin, a secreted small leucine-rich proteoglycan, acts as a tumor repressor in a variety of cancers, mainly by blocking the action of several receptor tyrosine kinases such the receptors for hepatocyte, epidermal and insulin-like growth factors. In the present study we investigated the effects of decorin in an experimental model of thioacetamide-induced hepatocarcinogenesis, and its potential role in modulating the signaling of platelet-derived growth factor receptor-α (PDGFRα). Genetic ablation of decorin led to enhanced tumor prevalence and higher tumor count as compared to wild-type animals. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21Waf1/Cip1 and concurrent activation (phosphorylation) of PDGFRα in the hepatocellular carcinomas generated in the decorin-null vis-à-vis wild-type mice. Notably, in normal liver PDGFRα localized primarily to the membrane of non-parenchymal cells, whereas in the malignant counterpart PDGFRα was expressed by the malignant cells at their cell surfaces. This process was facilitated by a genetic background lacking endogenous decorin. Double immunostaining of the proteoglycan and the receptor revealed only minor colocalization leading to the hypothesis that decorin would bind to the natural ligand PDGF rather than the receptor itself. Indeed, we found that decorin binds to PDGF using purified proteins and immune blot assays. Collectively, our findings support the idea that decorin acts as a secreted tumor repressor during hepatocarcinogenesis by hindering the action of another receptor tyrosine kinase such as the PDGFRα, and could be a novel therapeutic agent in the battle against liver cancer. © 2013 The Authors Journal compilation © 2013 FEBS.FEBS Journal 02/2013; · 3.79 Impact Factor -
Article: Decorin-TGFβ axis in hepatic fibrosis and cirrhosis.
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ABSTRACT: Hepatic fibrosis and cirrhosis are worldwide health care problems, especially in regions with a high rate of hepatitis infection. As these diseases affect a major part of the human population, the search for antifibrotic therapies has a high priority in medical research. Transforming growth factor β1 (TGF-β1) is one of the most powerful profibrotic cytokines. Thus, blocking TGF-β1 activity by natural inhibitors represents a valid and logical strategy to combat hepatic fibrosis. One of the natural inhibitors of TGF-β1 is decorin, a small leucine-rich proteoglycan that binds with high affinity to this cytokine and prevents its interaction with pro-fibrotic receptors. Recent evidence has shown that decorin has a protective role in liver fibrogenesis insofar as its genetic ablation in mice leads to enhanced matrix deposition, impaired matrix degradation, and "activation" of hepatic stellate cells, the main producers of fibrotic tissue. Moreover, TGF-β1 exerts a stronger effect when functional decorin is absent. These data provide robust genetic evidence for a direct role of endogenous decorin in preventing and retarding hepatic fibrosis. Thus, boosting the endogenous production of decorin or systemic delivery of recombinant decorin could represent an additional therapeutic modality against hepatic fibrosis.Journal of Histochemistry and Cytochemistry 01/2012; 60(4):262-8. · 2.72 Impact Factor -
Article: Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice
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ABSTRACT: Accumulation of connective tissue is a typical feature of chronic liver diseases. Decorin, a small leucine-rich proteoglycan, regulates collagen fibrillogenesis during development, and by directly blocking the bioactivity of transforming growth factor-β1 (TGFβ1), it exerts a protective effect against fibrosis. However, no in vivo investigations on the role of decorin in liver have been performed before. In this study we used decorin-null (Dcn−/−) mice to establish the role of decorin in experimental liver fibrosis and repair. Not only the extent of experimentally induced liver fibrosis was more severe in Dcn−/− animals, but also the healing process was significantly delayed vis-à-vis wild-type mice. Collagen I, III, and IV mRNA levels in Dcn−/− livers were higher than those of wild-type livers only in the first 2 months, but no difference was observed after 4 months of fibrosis induction, suggesting that the elevation of these proteins reflects a specific impairment of their degradation. Gelatinase assays confirmed this hypothesis as we found decreased MMP-2 and MMP-9 activity and higher expression of TIMP-1 and PAI-1 mRNA in Dcn−/− livers. In contrast, at the end of the recovery phase increased production rather than impaired degradation was found to be responsible for the excessive connective tissue deposition in livers of Dcn−/− mice. Higher expression of TGFβ1-inducible early responsive gene in decorin-null livers indicated enhanced bioactivity of TGFβ1 known to upregulate TIMP-1 and PAI-1 as well. Moreover, two main axes of TGFβ1-evoked signaling pathways were affected by decorin deficiency, namely the Erk1/2 and Smad3 were activated in Dcn−/− samples, whereas no significant difference in phospho-Smad2 was observed between mice with different genotypes. Collectively, our results indicate that the lack of decorin favors the development of hepatic fibrosis and attenuates its subsequent healing process at least in part by affecting the bioactivity of TGFβ1.Keywords: decorin; Erk1/2; liver fibrosis; MMP-2; MMP-9; TGFβ1Laboratory Investigation 10/2010; 91(3):439-451. · 3.64 Impact Factor -
Article: Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice.
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ABSTRACT: Accumulation of connective tissue is a typical feature of chronic liver diseases. Decorin, a small leucine-rich proteoglycan, regulates collagen fibrillogenesis during development, and by directly blocking the bioactivity of transforming growth factor-β1 (TGFβ1), it exerts a protective effect against fibrosis. However, no in vivo investigations on the role of decorin in liver have been performed before. In this study we used decorin-null (Dcn-/-) mice to establish the role of decorin in experimental liver fibrosis and repair. Not only the extent of experimentally induced liver fibrosis was more severe in Dcn-/- animals, but also the healing process was significantly delayed vis-à-vis wild-type mice. Collagen I, III, and IV mRNA levels in Dcn-/- livers were higher than those of wild-type livers only in the first 2 months, but no difference was observed after 4 months of fibrosis induction, suggesting that the elevation of these proteins reflects a specific impairment of their degradation. Gelatinase assays confirmed this hypothesis as we found decreased MMP-2 and MMP-9 activity and higher expression of TIMP-1 and PAI-1 mRNA in Dcn-/- livers. In contrast, at the end of the recovery phase increased production rather than impaired degradation was found to be responsible for the excessive connective tissue deposition in livers of Dcn-/- mice. Higher expression of TGFβ1-inducible early responsive gene in decorin-null livers indicated enhanced bioactivity of TGFβ1 known to upregulate TIMP-1 and PAI-1 as well. Moreover, two main axes of TGFβ1-evoked signaling pathways were affected by decorin deficiency, namely the Erk1/2 and Smad3 were activated in Dcn-/- samples, whereas no significant difference in phospho-Smad2 was observed between mice with different genotypes. Collectively, our results indicate that the lack of decorin favors the development of hepatic fibrosis and attenuates its subsequent healing process at least in part by affecting the bioactivity of TGFβ1.Laboratory Investigation 10/2010; 91(3):439-51. · 3.64 Impact Factor -
Article: Altered Proteoglycan Gene Expression in Human Biliary Cirrhosis
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ABSTRACT: Proteoglycans play key roles in the physiological assembly of extracellular matrices and in the modulation of growth factor activities. During liver regeneration there is a profound remodelling of the connective tissue network with a concurrent alteration in proteoglycan gene expression. In the present study we have analyzed in detail the biochemical and molecular properties of the proteoglycans associated with biliary cirrhosis. The three major proteoglycans of human liver, namely decorin, syndecan and perlecan, were markedly elevated in the cirrhotic parenchyma as compared to normal liver tissue. Particularly elevated (eight fold) was the perlecan. This proteoglycan had not only heparan sulfate but also chondroitin and der-matan sulfate. Reverse transcriptase PCR revealed a marked enhancement of decorin and syndecan expression and detectable message for perlecan was found only in the cirrhotic liver. These results indicate that significant proteoglycan alterations are associated with the development of biliary cirrhosis and provide basis for future studies aimed at the characterization of the molecular events involved in the regulation of extracellular matrix deposition in this common human disease.Pathology & Oncology Research 02/1997; 3(1):51-58. · 1.37 Impact Factor
Top co-authors
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Institutions
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1997–2013
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Semmelweis University
- First Department of Pathology and Experimental Cancer Research
Budapest, Budapest fovaros, Hungary
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1997–2010
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Thomas Jefferson University
- Kimmel Cancer Center
Philadelphia, PA, USA
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