title: Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice.
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.
  
  
  CONCLUSIONS
  Our data identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation-associated liver carcinogenesis.
authors.affiliation: Division of Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pusterla
authors.forename: Julia
authors.initials: J
authors.lastname: Nèmeth
authors.forename: Ilan
authors.initials: I
authors.lastname: Stein
authors.forename: Lars
authors.initials: L
authors.lastname: Wiechert
authors.forename: David
authors.initials: D
authors.lastname: Knigin
authors.forename: Silke
authors.initials: S
authors.lastname: Marhenke
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Varun
authors.initials: V
authors.lastname: Kumar
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D024243:HMGB1 Protein / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008103:Liver Cirrhosis / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000502:physiology*; D013234:Stem Cells / Q000473:pathology / Q000502:physiology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000097202:ATP-Binding Cassette Sub-Family B Member 4