Mutated K-ras(Asp12) promotes tumourigenesis in Apc(Min) mice more in the large than the small intestines, with synergistic effects between K-ras and Wnt pathways

Feijun Luo, David G Brooks, Hongtao Ye, Rifat Hamoudi, George Poulogiannis, Charles E Patek, Douglas J Winton, Mark J Arends

Research output: Contribution to journalArticlepeer-review

Abstract

Summary K-ras mutations are found in 40-50% of human colorectal adenomas and carcinomas, but their functional contribution remains incompletely understood. Here, we show that a conditional mutant K-ras mouse model (K-ras(Asp12)/Cre), with transient intestinal Cre activation by beta-Naphthoflavone (beta-NF) treatment, displayed transgene recombination and K-ras(Asp12) expression in the murine intestines, but developed few intestinal adenomas over 2 years. However, when crossed with Apc(Min/+) mice, the K-ras(Asp12)/Cre/Apc(Min/+) offspring showed acceleration of intestinal tumourigenesis with significantly changed average lifespan (P <0.05) decreased to 18.4 +/- 5.4 weeks from 20.9 +/- 4.7 weeks (control Apc(Min/+) mice). The numbers of adenomas in the small intestine and large intestine were significantly (P <0.01) increased by 1.5-fold and 5.7-fold, respectively, in K-ras(Asp12)/Cre/Apc(Min/+) mice compared with Apc(Min/+) mice, with the more marked increase in adenoma prevalence in the large intestine. To explore possible mechanisms for K-ras(Asp12) and Apc(Min) co-operation, the Mitogen-activated protein kinase (Mapk), Akt and Wnt signalling pathways, including selected target gene expression levels, were evaluated in normal large intestine and large intestinal tumours. K-ras(Asp12) increased activation of Mapk and Akt signalling pathway targets phospho-extracellular signal-regulated kinase (pErk) and pAkt, and increased relative expression levels of Wnt pathway targets vascular endothelial growth factor (VEGF), gastrin, cyclo-oxygenase 2 (Cox2) and T-cell lymphoma invasion and metastasis 1 (Tiam1) in K-ras(Asp12)/Cre/Apc(Min/+) adenomas compared with that of Apc(Min/+) adenomas, although other Wnt signalling pathway target genes such as Peroxisome proliferator-activated receptor delta (PPARd), matrix metalloproteinase 7 (MMP7), protein phosphatase 1 alpha (PP1A) and c-myc remained unchanged. In conclusion, intestinal expression of K-ras(Asp12) promotes mutant Apc-initiated intestinal adenoma formation in vivo more in the large intestine than the small intestine, with evidence of synergistic co-operation between mutant K-ras and Apc involving increased expression of some Wnt-pathway target genes.
Original languageEnglish
Pages (from-to)558-74
Number of pages17
JournalInternational Journal of Experimental Pathology
Volume90
Issue number5
DOIs
Publication statusPublished - Oct 2009

Keywords

  • Adenoma
  • Adenomatous Polyposis Coli Protein
  • Animals
  • Base Sequence
  • Cell Transformation, Neoplastic
  • DNA, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Genes, ras
  • Genotype
  • Intestinal Neoplasms
  • Intestine, Large
  • Intestine, Small
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Neoplasm Proteins
  • Oncogene Protein p21(ras)
  • Proto-Oncogene Proteins p21(ras)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Wnt Proteins

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