title: RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer.
abstract: Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Schneider
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Gautheron
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Feoktistova
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Roderburg
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Sven H
authors.initials: SH
authors.lastname: Loosen
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Sanchari
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Benz
authors.affiliation: Department of Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.affiliation: Department of Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.affiliation: Department of Medical Biology, Walter and Eliza Hall Institute of Medical Research and University of Melbourne, Parkville, VIC 3050/3052, Australia.
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
authors.affiliation: Department of Visceral and Transplantation Surgery, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Ulf P
authors.initials: UP
authors.lastname: Neumann
authors.affiliation: Department of Laboratory Animal Research, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Tolba
authors.affiliation: Department of Cardiology, University Hospital, 24105 Kiel, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Luedde
authors.affiliation: INSERM, UMR-1162, Functional Genomic of Solid Tumors, 75010 Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Panayotova-Dimitrova
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Leverkus
authors.affiliation: Proteomics Facility, IZKF, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Preisinger
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Pathology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: mvucur@ukaachen.de.
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.affiliation: Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: tluedde@ukaachen.de.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; C101338:PSMD2 protein, human; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex
keywords: HCC; NF-κB; RIP1; RIP3; RIPK3; apoptosis; cIAP-1; caspase-8; hepatocarcinogenesis; necroptosis