PMID- 11577000
OWN - NLM
STAT- MEDLINE
DCOM- 20011204
LR  - 20210103
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 22
IP  - 10
DP  - 2001 Oct
TI  - DNA hypermethylation is a mechanism for loss of expression of the HLA class I 
      genes in human esophageal squamous cell carcinomas.
PG  - 1615-23
AB  - 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 
      p21(Waf1) 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.
FAU - Nie, Y
AU  - Nie Y
AD  - Laboratory for Cancer Research, College of Pharmacy, Rutgers-The State University 
      of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
FAU - Yang, G
AU  - Yang G
FAU - Song, Y
AU  - Song Y
FAU - Zhao, X
AU  - Zhao X
FAU - So, C
AU  - So C
FAU - Liao, J
AU  - Liao J
FAU - Wang, L D
AU  - Wang LD
FAU - Yang, C S
AU  - Yang CS
LA  - eng
GR  - CA 72030/CA/NCI NIH HHS/United States
GR  - CA65781/CA/NCI NIH HHS/United States
GR  - ES 05022/ES/NIEHS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (DNA Primers)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (RNA, Messenger)
RN  - 776B62CQ27 (Decitabine)
RN  - EC 2.1.1.- (DNA Modification Methylases)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Azacitidine/*analogs & derivatives/*pharmacology
MH  - Carcinoma, Squamous Cell/*genetics/pathology
MH  - Chromosomes, Human, Pair 6/genetics
MH  - CpG Islands
MH  - *DNA Methylation
MH  - DNA Modification Methylases/antagonists & inhibitors
MH  - DNA Primers/chemistry
MH  - DNA, Neoplasm/metabolism
MH  - Decitabine
MH  - Down-Regulation
MH  - Esophageal Neoplasms/*genetics/pathology
MH  - Gene Deletion
MH  - *Genes, MHC Class I
MH  - Histocompatibility Antigens Class I/*genetics/metabolism
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - Loss of Heterozygosity
MH  - Microsatellite Repeats/genetics
MH  - RNA, Messenger/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2001/09/29 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/09/29 10:00
PHST- 2001/09/29 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/09/29 10:00 [entrez]
AID - 10.1093/carcin/22.10.1615 [doi]
PST - ppublish
SO  - Carcinogenesis. 2001 Oct;22(10):1615-23. doi: 10.1093/carcin/22.10.1615.