PRDX6 promotes tumor development via the JAK2/STAT3 pathway in a urethane-induced lung tumor model |
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| Institution: | 1. Functional Proteomics Laboratory, Department of Life Sciences, University of Siena, Siena, Italy;2. CIBIO, University of Trento, Trento, Italy;3. Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy;4. Department of Clinical Genetics, Human Genetics & Genome Research Division, Center of Excellence for Human Genetics, National Research Centre, Cairo, Egypt;1. Department of Oncology, Haematology, Hubertus Wald-Tumour Zentrum (UCCH), University Hospital Eppendorf (UKE), Hamburg, Germany;2. Center for Chemical Biology, Indian Institute of Chemical Technology (IICT), Hyderabad, India;3. Centre for Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India;4. Department of Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany;5. Interfacultary Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany;6. Prostate Cancer Centre, University Hospital Eppendorf (UKE), Hamburg, Germany;7. Department of Haematology and Oncology, University Hospital of the RWTH Aachen, Aachen, Germany;8. Department of Urology, Nizam''s Institute of Medical Sciences (NIMS), Hyderabad, India;9. Division of Haematology, University Hospital Zurich, Zurich, Switzerland;1. Latner Thoracic Surgery Research Laboratories, University Health Network Toronto General Research Institute, Toronto, Ontario, Canada;2. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan;3. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada |
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| Abstract: | Peroxiredoxin 6 (PRDX6) is a bifunctional protein with both glutathione peroxidase (GPx) and iPLA2 activities. Even though several pathophysiological functions have been studied, the definitive role of PRDX6 in tumor growth is not clear. Here, we compared carcinogen-induced tumor growth in PRDX6-transgenic (Tg) mice and non-Tg mice to evaluate the roles of PRDX6 in lung tumor development. Urethane (1 g/kg)-induced tumor incidence in PRDX6-Tg mice was significantly higher compared to non-Tg mice. In the tumors of PRDX6-Tg mice, the activation of JAK2/STAT3 and STAT3 DNA binding were also increased, accompanied by increased GPx and iPLA2 activities. PRDX6 was colocalized with JAK2 in tumor tissues and lung cancer cells and also showed physical interaction with JAK2. We found that increasing levels of PRDX6 increase the activation of the JAK2/STAT3 pathway. Furthermore, PRDX6-Tg mice showed altered cytokine levels in the tumors, especially leading to increased CCL5 levels. We validated that the activation of JAK2 was also decreased in lung tumors of CCR5?/? mice, and CCL5 increased the JAK2/STAT3 pathway in the lung cancer cells. Thus, our findings suggest that PRDX6 promotes lung tumor development via its mediated and CCL5-associated activation of the JAK2/STAT3 pathway. |
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| Keywords: | PRDX6 JAK2 STAT3 Lung cancer GPx iPLA2 Free radicals |
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