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Hypermethylation-Associated Inactivation of Retinoic Acid Receptor ß in Human Esophageal Squamous Cell Carcinoma

Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey [Y. W., M. Z. F., J. L., G-Y. Y., Y. N., Y. S., C. S., C. S. Y.]; Department of Clinical Cancer Prevention, University of Texas, M. D. Anderson Cancer Center, Houston, Texas [X. X.]; and Laboratory for Cancer Research, Zhengzhou University, Henan, China [L-D. W.]

Purpose: The purpose of this study was to investigate the mechanism of altered retinoic acid receptor ß (RARß) expression during esophageal squamous carcinogenesis.

Experimental Design: Samples were collected from Linzhou, China. The hypermethylation of CpG islands in the promoter region of the RARß gene was examined by methylation-specific PCR in human esophageal squamous cell carcinoma (ESCC) samples, as well as in neighboring tissues with normal epithelium, basal cell hyperplasia, and dysplasia. RARß mRNA expression was determined by in situ hybridization. The DNA methyltransferase inhibitor 2'-deoxy-5-azacytidine was used to treat the ESCC cell line, and the DNA hypermethylation status and mRNA expression level were examined.

Results: Two of 17 (12%) normal, 9 of 21 basal cell hyperplasia (43%), 7 of 12 dysplasia (58%), and 14 of 20 ESCC (70%) samples had hypermethylation of the RARß promoter region. The loss of RARß mRNA expression was highly concordant with RARß promoter CpG island hypermethylation when individual samples were considered in the correlation analysis. Good statistical correlation between hypermethylation and loss of RARß expression was revealed. Frequencies of hypermethylation appeared to increase with the progression of carcinogenesis. In samples from the same patients, if hypermethylation was detected in earlier lesions, it was usually observed in more severe lesions. In the ESCC cell line KYSE 510, 2'-deoxy-5-azacytidine partially reversed CpG island hypermethylation and restored RARß mRNA expression.

Conclusions: The results suggest that hypermethylation of RARß promoter region is an important mechanism for RARß gene silencing in esophageal squamous carcinogenesis.

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