title: Wild-type K-ras has a tumour suppressor effect on carcinogen-induced murine colorectal adenoma formation.
abstract: K-ras mutations are found in ~40% of human colorectal adenomas and carcinomas and contribute to colorectal tumour formation at an early stage. Wild-type K-ras has been reported to be deleted in some tumours, but the consequences of changes in wild-type K-ras copy number for experimental colorectal carcinogenesis have not been investigated. To characterize the effects of K-ras copy number changes on formation of carcinogen-induced colorectal neoplasms in mice, wild-type (K-ras(+/+) ) and heterozygous K-ras exon 1 knockout (K-ras(+/-) ) mice were given 10 weekly treatments of 1, 2-dimethylhydrazine (DMH) to induce colorectal tumours. Colorectal expression levels of K-ras 4A and 4B transcripts in K-ras(+/-) mice were ~50% decreased compared with K-ras(+/+) mice. One year after DMH treatment, survival of K-ras(+/-) mice decreased from 88 to 82% compared with wild-type mice. Colorectal adenomas significantly increased from 0.52 ± 0.15 in K-ras(+/+) mice to 0.87 ± 0.14 in K-ras(+/-) mice (mean ± SEM per mouse, P < 0.01); total tumour volume increased 2.13-fold (P < 0.05). Comparing K-ras(+/+) with K-ras(+/-) murine adenomas, Ki-67-positive proliferating tumour cells significantly increased from 7.77 ± 0.64% to 9.15 ± 0.92% and cleaved caspase-3-positive apoptotic tumour cells decreased from 1.40 ± 0.37% to 0.80 ± 0.22% (mean ± SEM, P < 0.05 for both). No K-ras or B-raf mutations were detected in the adenomas. Immunohistochemical studies showed no significant changes in extracellular signal regulating kinase/mitogen-activated protein kinase (Erk/MapK) or PI3K/Akt pathway activation in the adenomas. In conclusion, the data collectively show that a 50% reduction in K-ras gene dosage and RNA expression promoted experimental colorectal tumourigenesis, consistent with wild-type K-ras having a tumour suppressor effect on carcinogen-induced murine colorectal adenoma formation.
authors.affiliation: Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Feijun
authors.initials: F
authors.lastname: Luo
authors.forename: George
authors.initials: G
authors.lastname: Poulogiannis
authors.forename: Hongtao
authors.initials: H
authors.lastname: Ye
authors.forename: Rifat
authors.initials: R
authors.lastname: Hamoudi
authors.forename: Gehong
authors.initials: G
authors.lastname: Dong
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.forename: Ashraf E K
authors.initials: AE
authors.lastname: Ibrahim
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000009:adverse effects; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D057898:Hemizygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: D025521:Tumor Suppressor Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D019813:1,2-Dimethylhydrazine
keywords: 1, 2-dimethylhydrazine; K-ras; adenoma; carcinogen; colorectal; mouse; wild-type