title: Constitutive gp130 activation rapidly accelerates the transformation of human hepatocytes via an impaired oxidative stress response.
abstract: Pro-inflammatory signaling pathways, especially interleukin 6 (IL-6), and reactive oxygen species (ROS) promote carcinogenesis in the liver. In order to elucidate the underlying oncogenic mechanism, we activated the IL-6 signal transducer glycoprotein 130 (gp130) via stable expression of a constitutively active gp130 construct (L-gp130) in untransformed telomerase-immortalized human fetal hepatocytes (FH-hTERT). As known from hepatocellular adenomas, forced gp130 activation alone was not sufficient to induce malignant transformation. However, additional challenge of FH-hTERT L-gp130 clones with oxidative stress resulted in 2- to 3-fold higher ROS levels and up to 6-fold more DNA-double strand breaks (DSB). Despite increased DNA damage, ROS-challenged FH-hTERT L-gp130 clones displayed an enhanced proliferation and rapidly developed colony growth capabilities in soft agar. As driving gp130-mediated oncogenic mechanism, we detected a decreased expression of antioxidant genes, in particular glutathione peroxidase 3 and apolipoprotein E, and an absence of P21 upregulation following ROS-conferred induction of DSB. In summary, an impaired oxidative stress response in hepatocytes with gp130 gain-of-function mutations, as detected in dysplastic intrahepatic nodules and hepatocellular adenomas, is one of the central oncogenic mechanisms in chronic liver inflammation.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Heim
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Gil-Ibanez
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Herden
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ann Christin
authors.initials: AC
authors.lastname: Parplys
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Borgmann
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, 24098 Kiel, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt-Arras
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Wege
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D050822:Cytokine Receptor gp130 / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology*; D051379:Mice; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019098:Telomerase / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D050822:Cytokine Receptor gp130; C509186:TERT protein, human; D019098:Telomerase
keywords: glycoprotein 130; hepatocyte transformation; interleukin 6; oxidative stress response; reactive oxygen species