Journal Article

DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas

Yan Nie, Guang-yu Yang, Yunlong Song, Xin Zhao, Chi So, Jie Liao, Li-Dong Wang and Chung S. Yang

in Carcinogenesis

Volume 22, issue 10, pages 1615-1623
Published in print October 2001 | ISSN: 0143-3334
Published online October 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.10.1615
DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas

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The three human leukocyte antigen (HLA) class I antigens, HLA-A, HLA-B and HLA-C, play important roles in the elimination of transformed cells by cytotoxic T cells. Frequent loss of expression of these antigens at the cell surface has been observed in many human cancers. Various mechanisms for post-transcriptional regulation have been proposed and tested but the molecular mechanisms for transcriptional regulation are not clear. We show by immunohistochemistry that the HLA class I antigens are absent in 26 of 29 (89%) samples of human esophageal squamous cell carcinomas (ESCC). Eleven of the 26 ESCC samples lost mRNA expression for at least one of the HLA genes, as shown by RT–PCR. DNA from the 29 pairs of ESCC and neighboring normal epithelium were examined for CpG island hypermethylation, homozygous deletion, microsatellite instability (MSI) and loss of heterozygosity (LOH). DNA from normal epithelial tissues had no detectable methylation of the CpG islands of any of these gene loci. Thirteen of 29 ESCC samples (45%) exhibited methylation of one or more of the three HLA loci and six samples (21%) exhibited methylation of all three loci. The HLA-B gene locus was most frequently methylated (38%). HLA-B mRNA expression in an ESCC cell line, where HLA-B was hypermethylated and did not express mRNA, was activated after treatment with 5-aza-2′-deoxycytidine. Homozygous deletion of these three gene loci was not observed. Relatively low rates of LOH and MSI were observed for the microsatellite markers D6S306, D6S258, D6S273 and D6S1666, close to the HLA-A, -B and -C loci, although a high ratio of LOH was observed at a nearby locus (represented by the markers D6S1051 and D6S1560), where the tumor suppressor gene p21Waf1 resides. A strong correlation between genetic alterations and mRNA inactivation was observed in the ESCC samples. Our results indicate that HLA class I gene expression was frequently down-regulated in ESCC at both the protein and mRNA levels and that hypermethylation of the promoter regions of the HLA-A, -B and -C genes is a major mechanism of transcriptional inactivation.

Keywords: BCH, basal cell hyperplasia; β2-M, β2-microglobin; ESCC, esophageal squamous cell carcinoma; GAPDH, glyceraldehyde phosphate dehydrogenase gene; HD, homozygous deletion; HLA, human leukocyte antigen; IHC, immunohistochemistry; LOH, loss of heterozygosity; MSI, microsatellite instability.

Journal Article.  7168 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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