Analysis of the ANA gene as a candidate for the chromosome 21q oral cancer susceptibility locus.
Loss of heterozygosity (LOH) on the long arm of chromosome 21 (21q) is observed in several human malignancies. We identified novel tumour suppressor loci on this region in primary oral squamous cell carcinomas (OSCCs). To further determine the role of 21q deletions in oral cavity tumorigenesis, 63 OSCCs were examined for LOH at 21q using 7 microsatellite markers. LOH was observed in 32 of 63 cases (50.8%) that were informative for at least one of the loci analysed. Two distinct deleted regions were identified at chromosomal region 21q11.1. The possible involvement of ANA (abundant in neuroepithelium area), a candidate tumour suppressor gene (TSG) located on 21q11.2--21.1, was also evaluated for 20 OSCCs and 9 OSCC-derived cell lines. 60% of tumours (12/20) and 88.9% (8/9 cell lines) showed absent or reduced mRNA gene expression; only one OSCC case had a nucleotide substitution in the ANA gene. Interestingly, the frequency of the suppressed ANA mRNA expression was greater in stage IV tumours than in earlier stages. In addition, re-expression of the ANA gene mRNA was induced in 4 cell lines after treatment with 5-aza-2'-deoxycytidine, a DNA demethylating agent. These findings demonstrate that there may be at least 2 distinct TSGs on 21q11.1; loss of ANA gene expression could be involved in the progression of human OSCC; and aberrant methylation of the ANA gene promoter may participate in the transcriptional silencing of the gene in oral cancer cells.
First Department of Oral and Maxillo-Facial Surgery, Tokyo Dental College, 1-2-2 Masago, Mihama-ku, Chiba 261-8502, Japan.
N
N
Yamamoto
K
K
Uzawa
T
T
Yakushiji
T
T
Shibahara
H
H
Noma
H
H
Tanzawa
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002891:Chromosomes, Human, Pair 21; D019175:DNA Methylation; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
C424522:BTG3 protein, human; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D000077209:Decitabine; D001374:Azacitidine