Receptor for advanced glycation endproducts (RAGE) is a key ... : Hepatology (original) (raw)

Liver Injury/Regeneration

Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice

Pusterla, Tobias1,*; Nèmeth, Julia1,*; Stein, Ilan2; Wiechert, Lars1; Knigin, David2; Marhenke, Silke3; Longerich, Thomas4; Kumar, Varun5; Arnold, Bernd6; Vogel, Arndt3; Bierhaus, Angelika5; Pikarsky, Eli2; Hess, Jochen7,8,*; Angel, Peter1,*

1_Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany_

2_Lautenberg Center for Immunology and Department of Pathology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel_

3_Department of Hepatology, Medical School Hannover, Hannover, Germany_

4_Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany_

5_Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany_

6_Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany_

7_Junior Research Group Molecular Mechanisms of Head and Neck Tumors, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany_

8_Research Group Experimental Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany_

Received September 3, 2012; accepted March 12, 2013.

Supported by the Cooperation in Cancer Research of the German Cancer Research Center and Israeli Ministry of Science, Culture and Sport (Ca-130 to P.A., J.H., and E.P., and Ca-147 to P.A. and E.P.), the Federal Ministry of Science, Education and Art (MWK Excellence Cluster Initiative to A.B., P.A., and J.H.), the German Research Foundation (SFB Transregio 77, to P.A., J.H., T.L., and A.V.), and the Dietmar Hopp Foundation (to J.H.). Financial support by the Helmholtz Alliance Preclinical Comprehensive Cancer Center.

*These authors contributed equally to this work.

Address reprint requests to: Jochen Hess, Experimental Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Email:[email protected]; fax: +49 (0) 6221 56 4641.

Potential conflict of interest: Nothing to report.

Additional Supporting Information may be found in the online version of this article.

Abstract

The receptor for advanced glycation endproducts (RAGE) is a multiligand 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 high-mobility group box 1 (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 preneoplastic Mdr2−/− livers RAGE ablation did not affect the onset of inflammation, premalignant 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 dietary regime. Conclusion: Our data identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation-associated liver carcinogenesis. (Hepatology 2013)