Genetic Controls of Susceptibility and Resistance to 4‐Nitroquinoline 1‐Oxide‐induced Tongue Carcinomas in Rats

Kitano, Motoo; Hirayama, Yoshikazu; Tanuma, Jun‐ichi; Matsuuchi, Hiroaki; Miura, Yoshiaki; Li, Tiejun; Semba, Ichiro; Ozaki, Hiroki S.; Kokubu, Teiji; Hatano, Hiromichi; Tada, Minoru; Kobayashi, Y.; Shisa, Hayase

doi:10.1111/j.1349-7006.1996.tb03116.x

Cited by 12 publications

(14 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dark Agouti (DA) rats are highly susceptible to 4NQO-induced tongue cancer (TC), whereas Wistar-Furth rats (WF) are very resistant (3,4). A genome-wide association study in F2 progeny of these 2 strains revealed 5 significant QTLs, namely Tscc1-5 ( Tcas1-5 in the Rat Genome Database), which account for differences in susceptibility to TC (2,5,6).…”

Section: Introductionmentioning

confidence: 99%

Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis

et al. 2013

Self Cite

View full text Add to dashboard Cite

Susceptibly to the induction of rat tongue cancer (TC) by oral 4-nitroquinoline 1-oxide (4NQO) exposure is a polygenic trait. Among several quantitative trait loci identified by crosses between TC-susceptible Dark Agouti (DA) rats and TC-resistant Wistar-Furth (WF) rats, we focused on tongue cancer susceptibility locus (Tcas3) of chromosome 4. We examined tongue carcinogenesis in the reciprocal congenic strains DA.WF-Tcas3 and WF.DA-Tcas3 and in their parental strains. The Tcas3DA allele, and not the Tcas3WF allele, significantly favored tumor latency, incidence and TC number/size. In genomic DNA of TCs induced in (DA × WF) F1 rats, the resistant Tcas3WF allele was frequently and selectively lost, particularly in larger tumors. Thus, we searched the possible candidate genes in the Tcas3 region using microarray analysis of TCs in F1 rats and revealed significant upregulation of 2 cancer-related genes, parathyroid hormone-like hormone (Pthlh) and Kras2. The relevance of the WF allele of Pthlh as a cancer modifier was indicated by 3 single nucleotide polymorphisms specific to this strain. In contrast, no consistent strain-specific variations were found in Kras2. Moreover, the plasma Ca2+ level was consistently higher in DA rats when compared to the level in WF rats bearing TCs; moreover, the Pthlh-mRNA expression level was >30-fold higher in TCs when compared to this level in the normal tongue mucosa. Immunostaining experiments showed strong PTHrP protein expression in TCs of DA rats, and the signal was intensified in larger TCs. Kras2 was also upregulated in TCs, but to a lesser degree than PTHrP. Thus, Pthlh is a promising candidate modifier gene in the development and progression of rat TCs.

show abstract

Section: Introductionmentioning

confidence: 99%

Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…The phenotypic effect of Tscc4 on the size of TCs was below a signifi cance level (lod score, 3.13). a Cited from Kitano et al [7] with copyright permission of the publisher. On RNO14, we mapped a fi fth QTL ( Tscc5 ) linked to the number of TCs.…”

Section: Qtl Determining Host Susceptibility To Tcsmentioning

confidence: 99%

“…WF) F 1 hybrid rats were examined for loss of heterozygosity (LOH) at each chromosomal region containing these QTL. This report reviews our extensive genetic analysis of rat 4NQO-induced TCs and discusses possible candidate genes with special reference to genetic alterations in TCs and the metabolic activation of the carcinogen [6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

“…We have established a rat model to dissect the genetic predisposition to TCs induced by a chemical carcinogen, 4-nitroquinoline 1-oxide (4NQO). The model is based on our observation that Dark-Agouti (DA) rats are extremely susceptible to TC by oral administration of 4NQO, while Wistar/Furth (WF) rats are resistant [6][7][8][9] . Tanuma To elucidate the genetic predisposition to TC, (DA !…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Predisposition to 4NQO-Induced Tongue Carcinogenesis in the Rat

Tanuma¹,

Hirano²,

Hirayama³

et al. 2005

Med Princ Pract

Self Cite

View full text Add to dashboard Cite

Objective: This study aims to elucidate the genetic basis of predisposition to 4-nitroquinoline 1-oxide (4NQO)-induced tongue cancers (TCs). Materials and Methods: We have reported that inbred Dark-Agouti (DA) strain rats were highly susceptible to 4NQO-induced TCs, whereas Wistar/Furth (WF) rats were resistant to tongue squamous cell carcinomas induced by oral administration of 4NQO. Using size and number of the tumours as quantitative parameters, responsible host loci were analysed by an interval mapping of F₂ intercross of DA and WF given carcinogenic regimen. Also, loss of heterozygosity (LOH) at these loci was analysed in tongue cancers in (DA × WF) F₁. Results: We identified and mapped 5 significant quantitative trait loci (QTL), the Tongue squamous cell carcinoma 1–5 (Tscc1–5), and several other suggestive QTL that determine susceptibility to 4NQO-induced TC. Study of TCs induced in (DA × WF)F₁ rats revealed a high frequency of LOH in the chromosomal regions of Tscc2, 3, and 4 and also of suggestive QTL on chromosomes 5 and 6. The fact that LOH was found only in larger TCs indicates that LOH occurred in the process of tumour progression. In most LOH, the allele of the resistant WF strain was lost, suggesting that these loci may encode tumour suppressor genes. In larger TCs, in addition to LOH, point mutations and the methylation of possible candidate genes were accumulated. Conclusion: These observations indicate that the 4NQO-induced TC in the rat is a multifactorial disease of a polygenic trait. This model will be useful to understand the complicated genetic basis of predisposition to oral cancers.

show abstract

“…Virtually 100% of DA rats given drinking water containing 0.001% 4NQO developed one or more large TC within 180 days of administration, whereas the Wistar/Furth (WF) strain of rats was much less susceptible. [5][6][7][8] In the previous study with reciprocal backcrosses between DA and WF rats, 7,8) DA rats were shown to have a semidominant susceptibility locus, Stc1 (Susceptibility to TC-1) on rat chromosome (RNO) 19, and WF rats, another semidominant resistance gene Rtc1 (Resistance to TC-1) on RNO1.In this study, to scrutinize further the genetic predisposition to TC in the rat, we studied F2 progeny between DA and WF strains by means of a composite interval mapping analysis. After several statistical trials, we employed a quantitative parameter for tumor number, TC >3 mm in diameter, rather than TC >5 mm.…”

mentioning

confidence: 99%

Five Quantitative Trait Loci Affecting 4‐Nitroquinoline 1‐Oxide‐induced Tongue Cancer in the Rat

Tanuma

Fujii

Hirano

et al. 2001

Japanese Journal of Cancer Research

Self Cite

View full text Add to dashboard Cite

In our previous study, Dark-Agouti (DA) rats were found to be highly susceptible to 4-nitroquinoline 1-oxide (4NQO)-induced tongue carcinoma (TC), whereas Wistar/Furth (WF) rats were barely susceptible. Interval mapping analysis of reciprocal backcross rats showed two quantitative trait loci (QTL) on rat chromosomes (RNO) 1 and 19. In the present study, a composite interval mapping analysis was applied to 4NQO-induced TC in 130 (DA × × × ×WF) F2 rats, demonstrating five independent QTL, Tongue squamous cell carcinoma 1-5 (Tscc1-5), responsible for phenotypic differences in the size and number of TCs in the two strains. Two of these QTL were mapped on RNO1, and the others were mapped on RNO4, 14, and 19. The DA allele at these loci consistently yielded semidominant susceptibility to TC. Out of the five loci detected in this F2 generation, Tscc1 and 2 were identical to Stc1 and Rtc1 described in our previous study, but the other three were novel. We propose a new nomenclature consistent with their function. Genome-wide screening of the F2 progeny also suggested the presence of three additional QTL on RNO5, 6, and 10. The possible roles of these loci in tongue carcinogenesis are discussed. Key words: Genetic susceptibility -QTL -Tongue cancer -Rat -4-Nitroquinoline 1-oxideTongue carcinoma (TC) is one of the most frequent malignancies in the head and neck region. An increase in TC has been reported in the Western world over the past ten years. TC has a poor prognosis because therapeutic strategies provide limited effects.1-4) For effective prevention of TC, it would be necessary to identify the genetically predisposed risk group. However, virtually nothing is known about the genetic predisposition to TC.Recently, we found that the Dark-Agouti (DA) strain of rats had an extremely high susceptibility to 4-nitroquinoline 1-oxide (4NQO)-induced squamous cell carcinoma of the tongue. Virtually 100% of DA rats given drinking water containing 0.001% 4NQO developed one or more large TC within 180 days of administration, whereas the Wistar/Furth (WF) strain of rats was much less susceptible. [5][6][7][8] In the previous study with reciprocal backcrosses between DA and WF rats, 7,8) DA rats were shown to have a semidominant susceptibility locus, Stc1 (Susceptibility to TC-1) on rat chromosome (RNO) 19, and WF rats, another semidominant resistance gene Rtc1 (Resistance to TC-1) on RNO1.In this study, to scrutinize further the genetic predisposition to TC in the rat, we studied F2 progeny between DA and WF strains by means of a composite interval mapping analysis. After several statistical trials, we employed a quantitative parameter for tumor number, TC >3 mm in diameter, rather than TC >5 mm. In addition to two quantitative trait loci (QTL) described in the previous study, three novel QTL have been found to affect TC susceptibility. These five QTL explain almost all phenotypic variations between the two strains. MATERIALS AND METHODS Animals and phenotypeThe origin of DA rats is related to Copenhagen rats, although there is n...

show abstract

Genetic Controls of Susceptibility and Resistance to 4‐Nitroquinoline 1‐Oxide‐induced Tongue Carcinomas in Rats

Cited by 12 publications

References 7 publications

Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis

Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis

Genetic Predisposition to 4NQO-Induced Tongue Carcinogenesis in the Rat

Five Quantitative Trait Loci Affecting 4‐Nitroquinoline 1‐Oxide‐induced Tongue Cancer in the Rat

Contact Info

Product

Resources

About