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

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

Research output: Contribution to journalArticlepeer-review

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-ras(tmDelta4A/tmDelta4A)) that can express the K-ras 4B isoform only, along with heterozygous K-ras(tmDelta4A/+) 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-ras(tmDelta4A/tmDelta4A) 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-ras(tmDelta4A/tmDelta4A) mice compared with K-ras(tmDelta4A/+) and wild-type mice. Immunohistochemical studies showed that adenomas of K-ras(tmDelta4A/tmDelta4A) 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-ras(tmDelta4A/+) 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.
Original languageEnglish
Pages (from-to)542-50
Number of pages9
JournalThe Journal of Pathology
Volume220
Issue number5
DOIs
Publication statusPublished - Apr 2010

Keywords

  • 1,2-Dimethylhydrazine
  • Adenoma
  • Animals
  • Apoptosis
  • Carcinogens
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms
  • Enzyme Activation
  • Exons
  • Genes, Tumor Suppressor
  • Genes, ras
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins p21(ras)

Fingerprint Dive into the research topics of 'K-ras exon 4A has a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation'. Together they form a unique fingerprint.

Cite this