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Published ahead of print on March 23, 2004, doi:10.1165/rcmb.2003-0409OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 2, August 2004, 147-153

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Submitted on November 13, 2003
Revised on March 22, 2004

Ultrastructural and chromosomal studies of manganese superoxide dismutase in malignant mesothelioma

Vuokko Liisa Kinnula1*, Tuula Torkkeli2, Paula Kristo2, Raija Sormunen3, Ylermi Soini4, Paavo Paakko4, Tiina Ollikainen5, Katriina Kahlos6, Ari Hirvonen5, and Sakari Knuutila2

1 Department of Medicine, Pulmonary Division, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, 2 Departments of Pathology and Medical Genetics, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, 3 Department of Pathology, University of Oulu, Oulu, Finland; Biocenter of Oulu, Oulu, Finland, 4 Department of Pathology, University of Oulu, Oulu, Finland, 5 Finnish Institute of Occupational Health, Helsinki, Finland, 6 Department of Internal Medicine, University of Oulu, Oulu, Finland

* To whom correspondence should be addressed. E-mail: vuokko.kinnula{at}helsinki.fi.

Mesothelioma represents an aggressive tumor type with high resistance to all treatment modalities. Its pathogenesis is strongly associated with exposure to asbestos fibers and probably with free radicals. One of the most important free radical scavenging enzymes, mitochondrial manganese superoxide dismutase (MnSOD) has been shown to be elevated in mesothelioma (Kahlos K et al 1998, Am J Resp Cell Mol Biol 18:570-580 (1)). In the present study, we could detect intense ultrastructural accumulation of MnSOD in the mitochondrial compartment of malignant mesothelioma cells. There was no association between the immunohistochemical reactivity and the most common and functional polymorphic variant of MnSOD, the Ala to Val amino acid change at 9 position (16th amino acid from the beginning of the signal sequence), in the 31 mesothelioma cases investigated. Comparative genomic hybridization and fluorescence in situ hybridization did not reveal any changes in chromosome 6, where the MnSOD gene is located. Sequencing of the MnSOD promoter region in four mesothelioma cell lines showed similar nucleotide variables in the malignant and non-malignant cells. Therefore, the intense expression of MnSOD in the mitochondria of mesotelioma cells does not appear be associated with any major chromosomal alterations or the polymorphism of MnSOD gene. Association with oxidative/nitrosative stress in mesothelioma using nitrotyrosine immunostaining pointed to a tendency for more intense reactivity in those mesotheliomas with higher MnSOD expression (p=0.069)






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