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Molecular Biology, Pathobiology, and Genetics |
1 Department of Otolaryngology, Head and Neck Cancer Research Division and 2 Department of Genetic Medicine, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland and 3 Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
Requests for reprints: David Sidransky, Department of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, 818 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196. Phone: 410-502-5152; Fax: 410-614-1411; E-mail: dsidrans{at}jhmi.edu.
Promoter hypermethylation accompanied by gene silencing is a common feature of human cancers. We identified previously several new tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of reexpression on microarray analysis. In this study, we modified the selection of candidates from our previous microarray data by excluding genes that showed basal expression in cancer cell lines. With the new method, we found novel methylated genes with 90% accuracy. Among these 33 novel methylated genes that we identified in esophageal squamous cell carcinoma (ESCC) cell lines, N-methyl-D-aspartate receptor type 2B (NMDAR2B) was of particular interest. NMDAR2B was methylated in 95% of primary human ESCC tissue specimens and 12 ESCC cell lines by sequence analysis. NMDAR2B expression was silenced in all 12 ESCC cell lines and was reactivated by the demethylating agent 5-aza-2'-deoxycytidine. Moreover, reintroduction of the gene was accompanied by marked Ca2+-independent apoptosis in ESCC cell lines, suggesting that NMDAR2B can suppress tumor growth. Thus, NMDAR2B promoter methylation is common in ESCC, abrogating gene transcription and leading to cellular resistance to apoptosis. (Cancer Res 2006; 66(7): 3409-18)
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