Abstract
Apc-mutated Pirc rats, spontaneously developing intestinal tumours, are resistant to 1,2-dimethylhydrazine- (DMH-) induced colon apoptosis. To understand this phenomenon, we analyzed the expression of genotoxic stress-related genes Mgmt, Gsta1, and Gstp1 in the colon of wt and Pirc rats in basal conditions and 24 h after DMH; plasmatic oxidant/antioxidant status was also evaluated. After DMH, Mgmt expression was increased in both genotypes but significantly only in wt rats; Gsta1 expression was significantly increased in both genotypes. Gstp1 expression did not vary after DMH but was lower in Pirc rats. Moreover, for each genotype, we studied by microarray technique whole gene expression profile after DMH. By unsupervised cluster analysis, 28 genes were differentially modulated between the two genotypes. Among them were interferon-induced genes Irf7, Oas1a, Oasl2, and Isg15 and the transcription factor Taf6l, overexpressed in DMH-treated wt rats and unchanged in Pirc rats. RT-PCR confirmed their overexpression in DMH-treated wt rats and showed a slighter variation in DMH-treated Pirc rats. Taken together, despite a blunted induction of Irf7, Oas1a, and Mgmt, defective apoptosis in Pirc rats 24 h after DMH is not mirrored by major differences in gene expression compared with wt rats.
Highlights
IntroductionFailure to properly respond to cytotoxic insults (resistance to apoptosis) has been linked to carcinogenesis in various organs including colon [1]
Failure to properly respond to cytotoxic insults has been linked to carcinogenesis in various organs including colon [1]
Considering separately each genotype, we noted that Mgmt expression was significantly higher in DMHtreated wt rats compared with their basal values (t-test), while considering Pirc rats DMH effect was not significant
Summary
Failure to properly respond to cytotoxic insults (resistance to apoptosis) has been linked to carcinogenesis in various organs including colon [1]. [4], we showed that Pirc rats, mutated in Apc and spontaneously developing large and small intestinal tumours [5], are resistant to apoptosis induced by 1,2-dimethylhydrazine (DMH), an alkylating chemical inducing oxidative damage [6, 7], which is widely used to induce colon cancer in rodents [8]. To understand the mechanisms through which Apc gene affects the response to DMH, we thought it of interest to study in wt and Pirc rats the expression of some genes involved in repair of DNA damage and in the detoxification of chemicals, namely, Mgmt (O6methylguanine-DNA methyltransferase), Gsta (glutathioneS-transferase-a1), and Gstp (glutathione-S-transferase-p1) in basal conditions and 24 h after DMH. Since the ability to respond to DMH may be due, at least in part, to the antioxidant activity present in the plasma, we measured the antioxidant potential in the plasma of these animals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
