BioProject

K-ras mutations are observed in around 40% human colorectal adenomas and carcinomas and contribute to the pathogenesis of human and rodent colorectal tumour formation. Previously, we developed and characterised a strain of transgenic mice with inducible intestinal epithelial expression of K-rasVal12 via a Cre/LoxP system. To evaluate the influence of mutant K-ras on carcinogen-induced colorectal tumourigenesis, we induced neoplastic alterations in the large intestines of wild-type and K-rasVal12 mice using the colon-selective carcinogen 1, 2-dimethylhydrazine (DMH), which has been widely used to study chemically induced colorectal tumours that are histopathologically similar to those observed in humans. K-rasVal12 expression significantly promoted DMH-induced colorectal tumourigenesis: the average life span of the mice decreased from 38.52±1.97 weeks for 40 wild-type mice to 32.42±2.17 weeks for 26 K-rasVal12 mice (mean+SEM, P<0.05) and the large intestinal tumours increased from 2.27±0.15 per wild-type mouse to 3.85±0.20 in K-rasVal12 mice (mean+SEM, P<0.01). Adenomas from DMH-treated K-rasVal12 mice showed significantly higher levels (10.9±1.69%) of Ki-67-positive proliferating cells compared with those from DMH-treated wild-type mice (7.77±1.15%) (mean+SD, P<0.01) and a mild increase in apoptotic nuclei staining for cleaved caspase-3 (1.94+0.51% compared with 1.15±0.34%, mean+SD, P<0.01). In the adenomas from DMH-treated K-rasVal12 mice, K-rasVal12 transgene recombination and expression were confirmed and shown to promote strong Erk and mild Akt activation compared with adenomas from DMH-treated wild-type mice. Microarray hybridization and cluster analysis demonstrated different expression profiles in adenomas from DMH-treated wild-type and DMH-treated K-rasVal12 mice, indicating involvement of different molecular mechanisms, but array-comparative genomic hybridisation analysis showed chromosome stability in both, with very few chromosome alterations observed in adenomas from either of the two groups. Taken together, these data show that mutant K-ras promotes DMH-induced colorectal tumourigenesis, conferring a proliferative effect, but does not alter chromosome stability in the tumours. Overall design: This study has 7 samples analysed, 4 Kras mutants and 3 controls, on the Illumina Mouse-6 Beadchip array.