Genetic and epigenetic control of 4NQO-induced tongue carcinogenesis in the rats
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Oral administration of 4-nitroquinoline l-oxide (4NQO) can induce a high incidence of tongue cancers (TCs) in rats; inbred Dark-Agouti (DA) strain rats are highly susceptible, whereas Wistar/Furth (WF) rats are resistant. Our earlier studies confirmed that susceptibility depended on the respective genetic background, and 5 quantitative trait loci (QTLs), Tongue squamous cell carcinoma 1-5 (Tsccl-5), were identified as influencing susceptibility/resistance to 4NQO-induced TCs; however, the gene products encoded by the Tscc loci, and the molecular mechanisms responsible for their allele-specific cancer-modifier activities, remain unknown. To test whether Tscc genes display either oncogene or allele-specific tumour suppressor-like activity in TCs, we examined 4NQO-induced TCs in (DA x WF) Fl rats for loss of heterozygosity (LOH) at the loci known to be involved in cancer to characterize genetic alterations in TCs and their possible relationship with the Tscc loci. We examined 40 tongue tumours ≥ 5mm in diameter from (DA x WF) Fl rats for LOH at the Tscc loci, revealing a high frequency of LOH in chromosomal regions where the Tscc 2, 3 and 4 loci map. In most LOH, the allele of the resistant WF strain was lost, suggesting that these loci encode tumour suppressor genes. LOH was frequently found on rat chromosomes 5 (RNO5) and 6 (RNO6). In some advanced TCs, 5' CpG island methylation and mutation of p15^<INK4B> and p16^<INK4A> genes were also detected. The accumulation of LOH, mutation and methylation in tumour suppressor genes in larger tumours suggests that they may play a role in TC progression. This latest work represents an important step toward the identification of clinically significant biomarkers for tongue carcinogenesis.
- 鹿児島大学の論文
- 2006-03-25
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関連論文
- Genetic Controls of Susceptibility and Resistance to 4-Nitroquinoline 1-Oxide-induced Tongue Carcinomas in Rats
- Expressions of junB and c-fos are enhanced in 4-nitroquinoline 1-oxide-induced rat tongue cancers
- Five Quantitative Trait Loci Affecting 4-Nitroquinoline 1-Oxide-induced Tongue Cancer in the Rat
- Genetic and epigenetic control of 4NQO-induced tongue carcinogenesis in the rats