| First Author | Luo F | Year | 2011 |
| Journal | J Pathol | Volume | 223 |
| Issue | 3 | Pages | 390-9 |
| PubMed ID | 21171084 | Mgi Jnum | J:169019 |
| Mgi Id | MGI:4939549 | Doi | 10.1002/path.2790 |
| Citation | Luo F, et al. (2011) Mutant K-ras promotes carcinogen-induced murine colorectal tumourigenesis, but does not alter tumour chromosome stability. J Pathol 223(3):390-9 |
| abstractText | K-ras (KRAS) mutations are observed in around 40% of human colorectal adenomas and carcinomas. Previously, we developed and characterized a strain of transgenic mice with inducible intestinal epithelial expression of K-ras{Val12} 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-ras{Val12} mice using the colon-selective carcinogen 1,2-dimethylhydrazine (DMH), which has been widely used to induce colorectal tumours that are histopathologically similar to those observed in humans. K-ras{Val12} expression significantly promoted DMH-induced colorectal tumourigenesis: the average lifespan of the mice decreased from 38.52 +/- 1.97 weeks for 40 control mice to 32.42 +/- 2.17 weeks for 26 K-ras{Val12} mice (mean +/- SEM, p < 0.05) and the abundance of large intestinal tumours increased from 2.27 +/- 0.15 per control mouse to 3.85 +/- 0.20 in K-ras{Val12} mice (mean +/- SEM, p < 0.01). Adenomas from DMH-treated K-ras{Val12} mice showed significantly higher proportions of Ki-67-positive proliferating cells (10.9 +/- 0.69%) compared with those from DMH-treated wild-type mice (7.77 +/- 0.47%) (mean +/- SEM, p < 0.01) and a mild increase in apoptotic nuclei staining for cleaved caspase-3 (1.94 +/- 0.21% compared with 1.15 +/- 0.14%, mean +/- SEM, p < 0.01). In the adenomas from DMH-treated K-ras{Val12} mice, K-ras{Val12} transgene recombination and expression were confirmed, with immunohistochemical evidence of strong Erk/MapK and mild PI3K/Akt pathway activation compared with adenomas from DMH-treated wild-type mice. Microarray hybridization and clustering analysis demonstrated different expression profiles in adenomas from DMH-treated wild-type and DMH-treated K-ras{Val12} mice, indicating involvement of different molecular mechanisms including Erk/MapK and PI3K/Akt signalling in K-ras{Val12}-expressing adenomas. Array-comparative genomic hybridization analysis showed chromosome stability in both cohorts, with only a very few tiny alterations observed in one adenoma from a DMH-treated K-ras{Val12} mouse. Taken together, these data show that mutant K-ras significantly promotes DMH-induced colorectal tumourigenesis, resulting in distinct changes in cell signalling and proliferation, but does not alter chromosome stability in the tumours. |
