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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
Author(s) -
Luo Feijun,
Brooks David G.,
Ye Hongtao,
Hamoudi Rifat,
Poulogiannis George,
Patek Charles E.,
Winton Douglas J.,
Arends Mark J.
Publication year - 2009
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/j.1365-2613.2009.00667.x
Subject(s) - protein kinase b , mapk/erk pathway , biology , medicine , endocrinology , wnt signaling pathway , adenoma , kinase , microbiology and biotechnology , signal transduction , cancer research , chemistry
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 β‐Naphthoflavone (β‐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.