Ultrastructural and chromosomal studies on manganese superoxide dismutase in malignant mesothelioma

Our plain-English summary of Ultrastructural and chromosomal studies on manganese superoxide dismutase in malignant mesothelioma, by V.L. Kinnula, T. Torkkeli, P. Kristo, et al (American Journal of Respiratory Cell and Molecular Biology, 2004).

The study

• Authors: V.L. Kinnula, T. Torkkeli, P. Kristo, R. Sormunen, Y. Soini, P. Pääkkö, T. Ollikainen, K. Kahlos, A. Hirvonen, S. Knuutila
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2004;31(2):147-53
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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 (K. Kahlos et al., 1998, Am. J. Respir. Cell Mol. Biol. 18:570-580). 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 nonmalignant cells. Therefore, the intense expression of MnSOD in the mitochondria of mesothelioma 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).

In plain English

This laboratory study, which did not measure asbestos exposure, examined the antioxidant enzyme manganese superoxide dismutase (MnSOD) in malignant pleural mesothelioma. The authors stained 31 tumor biopsies and 10 frozen tumor samples and studied four mesothelioma cell lines and one nonmalignant line. MnSOD staining was high or moderate in 24 of 31 biopsies; none were negative. Staining was not significantly associated with survival or with a common alanine-to-valine MnSOD gene variant. Electron microscopy showed MnSOD concentrated in mesothelioma cells' mitochondria, with none detected in the cytoplasm. Chromosome tests on the cell lines found no copy-number changes in chromosome 6, where the MnSOD gene lies; FISH found two normal copies in each of three lines. Promoter (gene control region) variations were also seen in nonmalignant cells. A marker of oxidative and nitrosative stress (nitrotyrosine) tended to be stronger where MnSOD was higher, but not significantly (P value 0.069). The authors concluded that chromosome 6 alterations, as assessed by these tests, could not explain the high MnSOD and that a promoter variant or mutation was most unlikely to be the cause. They noted their methods could not rule out smaller changes, such as gene duplication.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: immunohistochemistry on tumor biopsies, electron and immunoelectron microscopy, Western blot, FISH and CGH chromosome analysis, gene genotyping and promoter sequencing in cell lines
• Who was studied: 31 biopsies of histopathologically confirmed malignant pleural mesothelioma from the pathology files of Oulu University Hospital, Finland (most previously published; four patients had received anticancer treatment before biopsy), plus 10 frozen mesothelioma tissues. Also four mesothelioma cell lines (M14K, M24K, M25K, M38K), the nonmalignant Met5-A mesothelial cell line, and lymphocyte DNA from 12 blood donors as controls. Dates not given.
• Exposure: No asbestos exposure was measured. The study examined expression of the enzyme MnSOD, its Ala to Val gene variant, chromosome 6 and the MnSOD promoter, and nitrotyrosine as a marker of oxidative/nitrosative stress.
• Main results:
  • In the 31 biopsies, MnSOD immunoreactivity was high or moderate in 24 cases. No biopsy was negative.
  • Survival of the patients was poor (mean 18 months, median 5 months, range 0 to 124 months). There was no significant association between MnSOD immunoreactivity and survival.
  • Of the 10 frozen specimens, MnSOD reactivity was high in five, moderate in three and weak in two.
  • In the mesothelioma specimens, MnSOD immunoreactivity was not significantly associated with the Ala/Val MnSOD gene variant (P value 0.30).
  • Nitrotyrosine, a marker of oxidative/nitrosative stress, tended to be associated with MnSOD. The association was not statistically significant (P value 0.069).
  • MnSOD levels were higher in the mesothelioma cell lines than in nonmalignant MeT-5A mesothelial cells.
  • Immunoelectron microscopy showed intense accumulation of MnSOD in the mitochondria of mesothelioma cells.
  • No MnSOD was detected in the cytoplasm of the mesothelioma cells.
  • FISH found two normal copies of chromosome 6 in three mesothelioma cell lines (M14K, M25K, M38K).
  • CGH found no copy number changes in chromosome 6 in any of the cell lines.
  • The nucleotide variations found in the MnSOD promoter region of the four mesothelioma cell lines were also seen in the nonmalignant control cells.
• The authors' conclusion: The authors concluded that chromosome 6 number changes or translocations, as assessed by CGH or FISH, could not explain MnSOD overexpression in mesothelioma. They also concluded that a promoter sequence variant or mutation was most unlikely to be the cause.
• Limitations the authors state:
  • The methods used could not rule out smaller molecular changes in chromosome 6, such as duplication of all or part of the MnSOD gene.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Superoxide, Malignant Mesothelioma, Mesothelioma, Fluorescence In Situ Hybridization (FISH).

Related studies

• Manganese superoxide dismutase genotypes and asbestos-associated pulmonary disorders — A. Hirvonen, J. Tuimala, et al. (2002)
• Manganese superoxide dismutase in healthy human pleural mesothelium and in malignant pleural mesothelioma — K. Kahlos, S. Anttila, et al. (1998)
• Manganese superoxide dismutase in human pleural mesothelioma cell lines — V.L. Kinnula, P. Pietarinen-Runtti, et al. (1996)
• Asbestos exposure, manganese superoxide dismutase (MnSOD) genotype, and lung cancer risk — L.I. Wang, D. Neuberg, et al. (2004)
• Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma — S. Landi, F. Gemignani, et al. (2007)
• Transfection of a manganese-containing superoxide dismutase gene into hamster tracheal epithelial cells ameliorates asbestos-mediated cytotoxicity — B.T. Mossman, P. Surinrut, et al. (1996)

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