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Wild‐type K‐ras has a tumour suppressor effect on carcinogen‐induced murine colorectal adenoma formation
Author(s) -
Luo Feijun,
Poulogiannis George,
Ye Hongtao,
Hamoudi Rifat,
Dong Gehong,
Zhang Wenyan,
Ibrahim Ashraf E. K.,
Arends Mark J.
Publication year - 2014
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/iep.12064
Subject(s) - carcinogenesis , colorectal cancer , adenoma , 1,2 dimethylhydrazine , wild type , apoptosis , medicine , colorectal adenoma , immunohistochemistry , biology , carcinogen , cancer research , endocrinology , cancer , azoxymethane , gene , genetics , mutant
Summary 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 PI 3K/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.