Genetic and epigenetic inactivation of extracellular superoxide dismutase promotes an invasive phenotype in human lung cancer by disrupting ECM homeostasis

Melissa LT Teoh-Fitzgerald, Matthew P. Fitzgerald, Taylor J. Jensen, Bernard W. Futscher, Frederick E. Domann

Research output: Contribution to journalArticle

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Abstract

Extracellular superoxide dismutase (EcSOD) is an important superoxide scavenger in the lung in which its loss, sequence variation, or abnormal expression contributes to lung diseases; however, the role of EcSOD in lung cancer has yet to be studied. We hypothesized that EcSOD loss could affect malignant progression in lung, and could be either genetic or epigenetic in nature. To test this, we analyzed EcSOD expression, gene copy number, promoter methylation, and chromatin accessibility in normal lung and carcinoma cells.Wefound that normal airway epithelial cells expressed abundant EcSOD and had an unmethylated promoter, whereas EcSOD-negative lung cancer cells displayed aberrant promoter hypermethylation and decreased chromatin accessibility. 5-aza-dC induced EcSOD suggesting that cytosine methylation was causal, in part, to silencing. In 48/50 lung tumors, EcSOD mRNA was significantly lower as early as stage I, and the EcSODpromoter was hypermethylated in 8/10 (80%) adenocarcinomas compared with 0/5 normal lung samples. In addition, 20% of the tumors showed loss of heterozygosity (LOH) of EcSOD. Reexpression of EcSOD attenuated the malignant phenotype of lung carcinoma cells by significantly decreasing invasion and survival. Finally, EcSOD decreased heparanase and syndecan-1 mRNAs in part by reducing NF-κB. By contrast, MnSOD and CuZnSOD showed no significant changes in lung tumors and had no effect on heparanase expression. Taken together, the loss of EcSOD expression is unique among the superoxide dismutases in lung cancer and is the result of EcSOD promoter methylation and LOH, suggesting that its early loss may contribute to ECM remodeling and malignant progression.

Original languageEnglish (US)
Pages (from-to)40-51
Number of pages12
JournalMolecular Cancer Research
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2012

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Epigenomics
Superoxide Dismutase
Lung Neoplasms
Homeostasis
Phenotype
Lung
Methylation
Loss of Heterozygosity
Chromatin
Syndecan-1
Carcinoma
Neoplasms
Messenger RNA
Gene Dosage
Cytosine
Superoxides
Lung Diseases
Adenocarcinoma
Epithelial Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Genetic and epigenetic inactivation of extracellular superoxide dismutase promotes an invasive phenotype in human lung cancer by disrupting ECM homeostasis. / Teoh-Fitzgerald, Melissa LT; Fitzgerald, Matthew P.; Jensen, Taylor J.; Futscher, Bernard W.; Domann, Frederick E.

In: Molecular Cancer Research, Vol. 10, No. 1, 01.01.2012, p. 40-51.

Research output: Contribution to journalArticle

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abstract = "Extracellular superoxide dismutase (EcSOD) is an important superoxide scavenger in the lung in which its loss, sequence variation, or abnormal expression contributes to lung diseases; however, the role of EcSOD in lung cancer has yet to be studied. We hypothesized that EcSOD loss could affect malignant progression in lung, and could be either genetic or epigenetic in nature. To test this, we analyzed EcSOD expression, gene copy number, promoter methylation, and chromatin accessibility in normal lung and carcinoma cells.Wefound that normal airway epithelial cells expressed abundant EcSOD and had an unmethylated promoter, whereas EcSOD-negative lung cancer cells displayed aberrant promoter hypermethylation and decreased chromatin accessibility. 5-aza-dC induced EcSOD suggesting that cytosine methylation was causal, in part, to silencing. In 48/50 lung tumors, EcSOD mRNA was significantly lower as early as stage I, and the EcSODpromoter was hypermethylated in 8/10 (80{\%}) adenocarcinomas compared with 0/5 normal lung samples. In addition, 20{\%} of the tumors showed loss of heterozygosity (LOH) of EcSOD. Reexpression of EcSOD attenuated the malignant phenotype of lung carcinoma cells by significantly decreasing invasion and survival. Finally, EcSOD decreased heparanase and syndecan-1 mRNAs in part by reducing NF-κB. By contrast, MnSOD and CuZnSOD showed no significant changes in lung tumors and had no effect on heparanase expression. Taken together, the loss of EcSOD expression is unique among the superoxide dismutases in lung cancer and is the result of EcSOD promoter methylation and LOH, suggesting that its early loss may contribute to ECM remodeling and malignant progression.",
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