Constitutive gp130 activation rapidly accelerates the transformation of human hepatocytes via an impaired oxidative stress response
| Autor: | Dirk Schmidt-Arras, Ann Christin Parplys, Henning Wege, Johannes Herden, Stefan Rose-John, Ansgar W. Lohse, Kerstin Borgmann, Ines Gil-Ibanez, D. Heim |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty GPX3 DNA damage interleukin 6 oxidative stress response Biology medicine.disease_cause Malignant transformation 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Internal medicine medicine Cytokine Receptor gp130 Animals Humans DNA Breaks Double-Stranded Telomerase chemistry.chemical_classification reactive oxygen species Reactive oxygen species Liver Neoplasms Hep G2 Cells glycoprotein 130 Cell biology Oxidative Stress 030104 developmental biology Endocrinology Cell Transformation Neoplastic Oncology chemistry 030220 oncology & carcinogenesis hepatocyte transformation Hepatocytes Female Signal transduction biological phenomena cell phenomena and immunity Carcinogenesis Oxidative stress Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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