Gene expression profile of colon mucosa after cytotoxic insult in wt and Apc -mutated pirc rats: Possible relation to resistance to apoptosis during carcinogenesis

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, over-expressed in DMH-treated wt, unchanged in Pirc rats. RT-PCR confirmed their over-expression 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.