K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

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Abstract
K‐ras encodes two isoforms, K‐ras 4A and 4B, that are jointly affected by K‐ras activating mutations, which are prevalent in colorectal cancer (CRC). CRC shows alterations in the expressed K‐ras 4A : 4B isoform ratio in favour of K‐ras 4B, in tumours both with and without K‐ras mutations. The present study evaluated whether K‐ras 4A expression can suppress colonic adenoma development in the absence of its oncogenic allele. Mice with homozygous targeted deletions of K‐ras exon 4A (K‐rastmΔ4A/tmΔ4A) that can express the K‐ras 4B isoform only, along with heterozygous K‐rastmΔ4A/+ and wild‐type mice, were given ten weekly 1,2‐dimethylhydrazine (DMH) treatments to induce colonic adenomas. There was a significant increase in both the number and the size of colonic adenomas in DMH‐treated K‐rastmΔ4A/tmΔ4A mice, with reduced survival, compared with heterozygous and wild‐type mice. No K‐ras mutations were found in any of the 30 tumours tested from the three groups. Lack of expression of K‐ras 4A transcripts was confirmed, whereas the relative expression levels of K‐ras 4B transcripts were significantly increased in the adenomas of K‐rastmΔ4A/tmΔ4A mice compared with K‐rastmΔ4A/+ and wild‐type mice. Immunohistochemical studies showed that adenomas of K‐rastmΔ4A/tmΔ4A mice had significantly increased cell proliferation and significantly decreased apoptosis with evidence of activation of MapKinase and Akt pathways, with increased phospho‐Erk1/2 and both phospho‐Akt‐Thr308 and phospho‐Akt‐Ser473 immunostaining, compared with adenomas from K‐rastmΔ4A/+ and wild‐type mice. In conclusion, following DMH treatment, K‐ras exon 4A deletion promoted increased number and size of colonic adenomas showing increased K‐ras 4B expression, increased proliferation, decreased apoptosis, and activation of MapKinase and Akt pathways, in the absence of K‐ras mutations. Therefore, K‐ras 4A expression had a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation, explaining the selective advantage of the altered K‐ras 4A : 4B isoform ratio found in human colorectal cancer. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Funding Information
  • Cancer Research UK and Wellcome Trust

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