University of Oulu

Konzack Anja, Jakupovic Mirza, Kubaichuk Kateryna, Görlach Agnes, Dombrowski Frank, Miinalainen Ilkka, Sormunen Raija, and Kietzmann Thomas. Antioxidants & Redox Signaling. November 2015, 23(14): 1059-1075. doi:10.1089/ars.2015.6318.

Mitochondrial dysfunction due to lack of manganese superoxide dismutase promotes hepatocarcinogenesis

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Author: Konzack, Anja1; Jakupovic, Mirza2; Kubaichuk, Kateryna1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, and Biocenter Oulu, University of Oulu, Oulu, Finland
2Department of Chemistry, University of Kaiserslautern, Kaiserslautern, Germany
3Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich, Munich, Germany
4Institute of Pathology, University of Greifswald, Greifswald, Germany
5Biocenter Oulu Electron Microscopy Core Facility, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.4 MB)
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Language: English
Published: Mary Ann Liebert, 2015
Publish Date: 2017-03-14


Aims: One of the cancer hallmarks is mitochondrial dysfunction associated with oxidative stress. Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (MnSOD). Accordingly, carcinogenesis would be associated with a dysregulation in MnSOD expression. However, the association studies available so far are conflicting, and no direct proof concerning the role of MnSOD as a tumor promoter or suppressor has been provided. Therefore, we investigated the role of MnSOD in carcinogenesis by studying the effect of MnSOD deficiency in cells and in the livers of mice.

Results: We found that loss of MnSOD in hepatoma cells contributed to their conversion toward a more malignant phenotype, affecting all cellular properties generally associated with metabolic transformation and tumorigenesis. In vivo, hepatocyte-specific MnSOD-deficient mice showed changed organ architecture, increased expression of tumor markers, and a faster response to carcinogenesis. Moreover, deficiency of MnSOD in both the in vitro and in vivo model reduced β-catenin and hypoxia-inducible factor-1 levels.

Innovation: The present study shows for the first time the important correlation between MnSOD presence and the regulation of two major pathways involved in carcinogenesis, the Wnt/β-catenin and hypoxia signaling pathway.

Conclusion: Our study points toward a tumor suppressive role of MnSOD in liver, where the Wnt/β-catenin and hypoxia pathway may be crucial elements.

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Series: Antioxidants & redox signaling
ISSN: 1523-0864
ISSN-E: 1557-7716
ISSN-L: 1523-0864
Volume: 23
Issue: 14
DOI: 10.1089/ars.2015.6318
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3122 Cancers
Funding: This work was supported by grants from CIMO, Biocenter Oulu, and the Sigrid Juselius Foundation.
Copyright information: © Anja Konzack et al. 2015; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.