Carcinogenesis Advance Access published online on December 4, 2003
Carcinogenesis, doi:10.1093/carcin/bgh038
© 2003 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CARCINOGENESIS
1 Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87 108
* Corresponding author. E-mail: sbelinsk{at}LRRI.org.
Received 5 September 2003
; revised 17 November 2003
; accepted 19 November 2003
The retinoic acid receptor beta (RAR-
promoter hypermethylation, cigarette smoke, NNK, vinyl carbamate, methylene chloride, retinoic acid receptor-Carcinogen exposure differentially modulates RAR-
promoter hypermethylation, an early and frequent event in mouse lung carcinogenesis
) gene encodes one of the primary receptors for retinoic acid, an important signaling molecule in lung growth, differentiation, and carcinogenesis. RAR- has been shown to be downregulated by methylation in human lung cancer. We have previously used lung tumors induced in mice to evaluate the timing and effect of specific carcinogen exposures on targeting genes altered in human lung cancer. These studies were extended to characterize the role of methylation of the RAR- gene in murine lung cancers. After treatment with the demethylating agent 5-aza-2'-deoxycytidine (DAC), RAR- was re-expressed in silenced cell lines or expressed at a higher rate than without DAC, supporting methylation as the inactivating mechanism. Bisulfite sequencing detected dense methylation in the area of the CpG island that contained the 5' untranslated region and the first translated exon in non-expressing cell lines, compared to minimal and heterogeneous methylation in normal mouse lung. Methylation-specific PCR revealed that this gene is targeted differentially by carcinogen exposures with the detection of methylated alleles in virtually all primary tumors associated with cigarette smoke or 4-methylnitrosamino-1-(3-pyridyl)-butanone (NNK) in contrast to half of tumors induced by methylene chloride or vinyl carbamate. RAR- methylation was also detected in 54% of preneoplastic hyperplasias induced by treatment with NNK. Bisulfite sequencing of both premalignant and malignant lesions detected dense methylation in the same area observed in cell lines, substantiating that this gene is functionally inactivated at the earliest histologic stage of adenocarcinoma development. These studies demonstrate that aberrant methylation of RAR- is an early and common alteration in murine lung tumors induced by several environmentally relevant exposures.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Song, B. Guan, T. Men, A. Hoque, R. Lotan, and X.-C. Xu Antitumor Effect of Retinoic Acid Receptor-{beta}2 Associated with Suppression of Cyclooxygenase-2 Cancer Prevention Research, March 1, 2009; 2(3): 274 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D.F. Licchesi, W. H. Westra, C. M. Hooker, and J. G. Herman Promoter Hypermethylation of Hallmark Cancer Genes in Atypical Adenomatous Hyperplasia of the Lung Clin. Cancer Res., May 1, 2008; 14(9): 2570 - 2578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Huang, Z. D. Liang, T.-T. Wu, A. Hoque, H. Chen, Y. Jiang, H. Zhang, and X.-c. Xu Tumor-Suppressive Effect of Retinoid Receptor-Induced Gene-1 (RRIG1) in Esophageal Cancer Cancer Res., February 15, 2007; 67(4): 1589 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Vuillemenot, J. A. Hutt, and S. A. Belinsky Gene Promoter Hypermethylation in Mouse Lung Tumors Mol. Cancer Res., April 1, 2006; 4(4): 267 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Petty, N. Li, A. Biddle, R. Bounds, C. Nitkin, Y. Ma, K. H. Dragnev, S. J. Freemantle, and E. Dmitrovsky A Novel Retinoic Acid Receptor {beta} Isoform and Retinoid Resistance in Lung Carcinogenesis J Natl Cancer Inst, November 16, 2005; 97(22): 1645 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hutt, B. R. Vuillemenot, E. B. Barr, M. J. Grimes, F. F. Hahn, C. H. Hobbs, T. H. March, A. P. Gigliotti, S. K. Seilkop, G. L. Finch, et al. Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways Carcinogenesis, November 1, 2005; 26(11): 1999 - 2009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vineis and K. Husgafvel-Pursiainen Air pollution and cancer: biomarker studies in human populations Carcinogenesis, November 1, 2005; 26(11): 1846 - 1855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Belinsky Silencing of genes by promoter hypermethylation: key event in rodent and human lung cancer Carcinogenesis, September 1, 2005; 26(9): 1481 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Maruya, J.-P. J. Issa, R. S. Weber, D. I. Rosenthal, J. C. Haviland, R. Lotan, and A. K. El-Naggar Differential Methylation Status of Tumor-Associated Genes in Head and Neck Squamous Carcinoma: Incidence and Potential Implications Clin. Cancer Res., June 1, 2004; 10(11): 3825 - 3830. [Abstract] [Full Text] [PDF]
|
|