Aberrant methylation accounts for cell adhesion-related gene silencing during 3-methylcholanthrene and diethylnitrosamine induced multistep rat lung carcinogenesis associated with overexpression of DNA methyltransferases 1 and 3a
To evaluate the significance of alterations in cell adhesion-related genes methylation during lung multistep carcinogenesis induced by the genotoxic carcinogens 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN), tissue samples microdissected from MCA/DEN-induced rat lung carcinogenesis model were subjected to methylation-specific PCR to evaluate the DNA methylation status of CADM1, TIMP3, E-cadherin and N-cadherin. Immunohistochemistry was used to determine protein expression of CADM1, TIMP3, N-cadherin and the DNA methyltransferases (DNMTs) 1, 3a and 3b. E-cadherin hypermethylation was not detected in any tissue. CADM1, TIMP3 and N-cadherin hypermethylation was correlated with the loss of their protein expression during the progression of pathologic lesions. The prevalence of DNA methylation of at least one gene and the average number of methylated genes increased with the histological progression. DNMT1 and DNMT3a protein expression increased progressively during the stages of lung carcinogenesis, whereas DNMT3b overexpression was only found in several samples. Furthermore, DNMT1 protein expression levels were correlated with CADM1 methylation, and DNMT3a protein expression levels were correlated with CADM1, TIMP3 and N-cadherin methylation. The average number of methylated genes during carcinogenesis was significantly correlated with DNMT1 and DNMT3a protein expression levels. Moreover, mRNA expression of CADM1 significantly increased after treatment with DNMT inhibitor 5-aza-2'-deoxycytidine in CADM1-methylated primary tumor cell lines. Our findings suggest that an accumulation of hypermethylation accounts for cell adhesion-related gene silencing is associated with dynamic changes in the progression of MCA/DEN-induced rat lung carcinogenesis. We suggest that DNMT1 and DNMT3a protein overexpression may be responsible for this aberrant DNA methylation.
- OSTI ID:
- 21535239
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 251, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.12.002; PII: S0041-008X(10)00451-5; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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3-METHYLCHOLANTHRENE
CARCINOGENESIS
CARCINOGENS
CARCINOMAS
DNA
GENES
LUNGS
MESSENGER-RNA
METHYL TRANSFERASES
METHYLATION
POLYMERASE CHAIN REACTION
RATS
TUMOR CELLS
ANIMAL CELLS
ANIMALS
AROMATICS
BODY
CARBON-GROUP TRANSFERASES
CHEMICAL REACTIONS
CONDENSED AROMATICS
DISEASES
ENZYMES
GENE AMPLIFICATION
HYDROCARBONS
MAMMALS
NEOPLASMS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PATHOGENESIS
POLYCYCLIC AROMATIC HYDROCARBONS
PROTEINS
RESPIRATORY SYSTEM
RNA
RODENTS
TRANSFERASES
VERTEBRATES