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Tobias Pusterla, Julia Németh,
Ilan Stein,
Lars Wiechert,
David Knigin,
Silke Marhenke,
Thomas Longerich,
Varun Kumar,
Bernd Arnold,
Arndt Vogel,
Angelika Bierhaus,
Eli Pikarsky,
Jochen Hess,
Peter Angel
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ABSTRACT: The Receptor for Advanced Glycation-End products (RAGE) is a multi-ligand receptor and member of the immunoglobulin superfamily. RAGE is mainly involved in tissue damage and chronic inflammatory disorders, sustaining the inflammatory response upon engagement with damage associated molecular pattern molecules (DAMPs) such as S100 proteins and HMGB1. Enhanced expression of RAGE and its ligands has been demonstrated in distinct tumors and several studies support its crucial role in tumor progression and metastasis by still unknown mechanisms. Here we show that RAGE supports hepatocellular carcinoma (HCC) formation in the Mdr2(-/-) mouse model, a prototype model of inflammation-driven HCC formation, which mimics the human pathology. Mdr2(-/-) Rage(-/-) (dKO) mice developed smaller and fewer HCCs than Mdr2(-/-) mice. Interestingly, although in pre-neoplastic Mdr2(-/-) livers RAGE ablation did not affect the onset of inflammation, pre-malignant dKO livers showed reduced liver damage and fibrosis, in association with decreased oval cell activation. Oval cells expressed high RAGE levels and displayed reduced proliferation upon RAGE silencing. Moreover, stimulation of oval cells with HMGB1 promoted an ERK1/2-Cyclin D1-dependent oval cell proliferation in vitro. Finally, genetic and pharmacologic blockade of RAGE signaling impaired oval cell activation in an independent mouse model of oval cell activation, the Choline Deficient Ethionine-supplemented (CDE) dietary regime. Conclusions: Our data have identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation-associated liver carcinogenesis. (HEPATOLOGY 2013.).
Hepatology 03/2013; · 11.66 Impact Factor
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Astrid Riehl,
Tobias Bauer,
Benedikt Brors,
Hauke Busch,
Regina Mark, Julia Németh,
Christoffer Gebhardt,
Angelika Bierhaus,
Peter Nawroth,
Roland Eils,
Rainer König,
Peter Angel,
Jochen Hess
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ABSTRACT: In the past, molecular mechanisms that drive the initiation of an inflammatory response have been studied intensively. However, corresponding mechanisms that sustain the expression of inflammatory response genes and hence contribute to the establishment of chronic disorders remain poorly understood. Recently, we provided genetic evidence that signaling via the receptor for advanced glycation end products (Rage) drives the strength and maintenance of an inflammatory reaction. In order to decipher the mode of Rage function on gene transcription levels during inflammation, we applied global gene expression profiling on time-resolved samples of mouse back skin, which had been treated with the phorbol ester TPA, a potent inducer of skin inflammation.
Ranking of TPA-regulated genes according to their time average mean and peak expression and superimposition of data sets from wild-type (wt) and Rage-deficient mice revealed that Rage signaling is not essential for initial changes in TPA-induced transcription, but absolutely required for sustained alterations in transcript levels. Next, we used a data set of differentially expressed genes between TPA-treated wt and Rage-deficient skin and performed computational analysis of their proximal promoter regions. We found a highly significant enrichment for several transcription factor binding sites (TFBS) leading to the prediction that corresponding transcription factors, such as Sp1, Tcfap2, E2f, Myc and Egr, are regulated by Rage signaling. Accordingly, we could confirm aberrant expression and regulation of members of the E2f protein family in epidermal keratinocytes of Rage-deficient mice.
In summary, our data support the model that engagement of Rage converts a transient cellular stimulation into sustained cellular dysfunction and highlight a novel role of the Rb-E2f pathway in Rage-dependent inflammation during pathological conditions.
BMC Genomics 10/2010; 11:537. · 4.07 Impact Factor
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Julia Németh,
Ilan Stein,
Daniel Haag,
Astrid Riehl,
Thomas Longerich,
Elad Horwitz,
Kai Breuhahn,
Christoffer Gebhardt,
Peter Schirmacher,
Meinhard Hahn,
Yinon Ben-Neriah,
Eli Pikarsky,
Peter Angel,
Jochen Hess
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ABSTRACT: The nuclear factor-kappaB (NF-kappaB) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-kappaB-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-kappaB-deficient and NF-kappaB-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-kappaB target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. CONCLUSION: We identified S100A8 and S100A9 as novel NF-kappaB target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death.
Hepatology 06/2009; 50(4):1251-62. · 11.66 Impact Factor
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Christoffer Gebhardt,
Astrid Riehl,
Moritz Durchdewald, Julia Németh,
Gerhard Fürstenberger,
Karin Müller-Decker,
Alexander Enk,
Bernd Arnold,
Angelika Bierhaus,
Peter P Nawroth,
Jochen Hess,
Peter Angel
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ABSTRACT: A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic inflammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer.
Journal of Experimental Medicine 03/2008; 205(2):275-85. · 13.85 Impact Factor
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ABSTRACT: Calprotectin (S100A8/A9), a heterodimer of the two calcium-binding proteins S100A8 and S100A9, was originally discovered as immunogenic protein expressed and secreted by neutrophils. Subsequently, it has emerged as important pro-inflammatory mediator in acute and chronic inflammation. More recently, increased S100A8 and S100A9 levels were also detected in various human cancers, presenting abundant expression in neoplastic tumor cells as well as infiltrating immune cells. Although, many possible functions have been proposed for S100A8/A9, its biological role still remains to be defined. Altogether, its expression and potential cytokine-like function in inflammation and in cancer suggests that S100A8/A9 may play a key role in inflammation-associated cancer.
Biochemical Pharmacology 12/2006; 72(11):1622-31. · 4.70 Impact Factor
