Mutant K-ras promotes carcinogen-induced murine colorectal tumourigenesis, but does not alter tumour chromosome stability

Feijun Luo, George Poulogiannis, Hongtao Ye, Rifat Hamoudi, Wenyan Zhang, Gehong Dong, Mark J Arends

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)390-9
Number of pages10
JournalThe Journal of Pathology
Volume223
Issue number3
DOIs
Publication statusPublished - Feb 2011

Keywords

  • 1,2-Dimethylhydrazine
  • Adenoma
  • Animals
  • Apoptosis
  • Carcinogens
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Chromosomal Instability
  • Cluster Analysis
  • Colorectal Neoplasms
  • Disease Models, Animal
  • Gene Expression Profiling
  • Genes, ras
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neoplasm Proteins
  • Oligonucleotide Array Sequence Analysis
  • beta Catenin

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