Journal article
Genetic and epigenetic inactivation of extracellular superoxide dismutase promotes an invasive phenotype in human lung cancer by disrupting ECM homeostasis
Molecular cancer research, Vol.10(1), pp.40-51
01/2012
DOI: 10.1158/1541-7786.MCR-11-0501
PMCID: PMC3262094
PMID: 22064654
Abstract
Extracellular superoxide dismutase (
EcSOD
) is an important superoxide scavenger in the lung where 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. We found 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
EcSOD
promoter was hypermethylated in 8/10 (80%) adenocarcinomas compared to 0/5 normal lung samples. In addition, 20% of the tumors showed LOH of
EcSOD
. Re-expression 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.
Details
- Title: Subtitle
- Genetic and epigenetic inactivation of extracellular superoxide dismutase promotes an invasive phenotype in human lung cancer by disrupting ECM homeostasis
- Creators
- Melissa L.T Teoh - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, 52242Matthew P Fitzgerald - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, 52242Taylor J Jensen - Department of Pharmacology and Toxicology, College of Pharmacy, and The Arizona Cancer Center, University of Arizona, Tucson, AZ 85724Bernard W Futscher - Department of Pharmacology and Toxicology, College of Pharmacy, and The Arizona Cancer Center, University of Arizona, Tucson, AZ 85724Frederick E Domann - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and The Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, 52242
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.10(1), pp.40-51
- DOI
- 10.1158/1541-7786.MCR-11-0501
- PMID
- 22064654
- PMCID
- PMC3262094
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Grant note
- R01 CA115438-05 || CA / National Cancer Institute : NCI R01 CA073612-10 || CA / National Cancer Institute : NCI R01 CA065662-13 || CA / National Cancer Institute : NCI R56 CA073612-11A1 || CA / National Cancer Institute : NCI R01 CA065662-14 || CA / National Cancer Institute : NCI R01 CA115438-04 || CA / National Cancer Institute : NCI
- Language
- English
- Date published
- 01/2012
- Academic Unit
- Pathology; Surgery; Radiation Oncology
- Record Identifier
- 9984047606902771
Metrics
27 Record Views