부산대학교 도서관

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. [ABSTRACT FROM AUTHOR]