Constitutive gp130 activation rapidly accelerates the transformation of human hepatocytes via an impaired oxidative stress response
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Denise Heim1,*, Ines Gil-Ibanez1,*, Johannes Herden1, Ann Christin Parplys2, Kerstin Borgmann2, Dirk Schmidt-Arras3, Ansgar W. Lohse1, Stefan Rose-John3, Henning Wege1
1Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
2Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
3Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, 24098 Kiel, Germany
*These authors have contributed equally to this work
Henning Wege, email: [email protected]
Keywords: interleukin 6, glycoprotein 130, reactive oxygen species, oxidative stress response, hepatocyte transformation
Received: March 01, 2016 Accepted: July 09, 2016 Published: July 30, 2016
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.
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