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Gene expression profile of calcium mediated prevention of colorectal cancer in a mouse model

ABSTRACT: To further elucidate the mechanism of calcium mediated chemoprevention of colorectal cancer,we have employed whole genome microarray expression profiling as a discovery platform to identify genes that differentially expressed in mice from high calcium group compared those from DMH group.The mice of DMH group were received normal diet (calcium concentration,1.24%) and subcutaneous injection of 1,2-Dimethylhydrazine at a dose of 20 mg/kg once weekly for 20 weeks,the mice of high calcium group were received high calcium diet(calcium concentration,3%) and subcutaneous injection of 1,2-Dimethylhydrazine at a dose of 20 mg/kg once weekly for 20 weeks.The mice were sarcrificed at 24 week.Nine normal colonic mucosa (3 from DMH group, 3 from high calcium group mice with tumors, and 3 from high calcium group mice without tumors) were used for the microarray analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE25680 | GEO | 2011/11/23

SECONDARY ACCESSION(S): PRJNA135827

REPOSITORIES: GEO

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Project description:K-ras mutations are observed in around 40% human colorectal adenomas and carcinomas and contribute to the pathogenesis of human and rodent colorectal tumour formation. Previously, we developed and characterised a strain of transgenic mice with inducible intestinal epithelial expression of K-rasVal12 via a Cre/LoxP system. To evaluate the influence of mutant K-ras on carcinogen-induced colorectal tumourigenesis, we induced neoplastic alterations in the large intestines of wild-type and K-rasVal12 mice using the colon-selective carcinogen 1, 2-dimethylhydrazine (DMH), which has been widely used to study chemically induced colorectal tumours that are histopathologically similar to those observed in humans. K-rasVal12 expression significantly promoted DMH-induced colorectal tumourigenesis: the average life span of the mice decreased from 38.52±1.97 weeks for 40 wild-type mice to 32.42±2.17 weeks for 26 K-rasVal12 mice (mean+SEM, P<0.05) and the large intestinal tumours increased from 2.27±0.15 per wild-type mouse to 3.85±0.20 in K-rasVal12 mice (mean+SEM, P<0.01). Adenomas from DMH-treated K-rasVal12 mice showed significantly higher levels (10.9±1.69%) of Ki-67-positive proliferating cells compared with those from DMH-treated wild-type mice (7.77±1.15%) (mean+SD, P<0.01) and a mild increase in apoptotic nuclei staining for cleaved caspase-3 (1.94+0.51% compared with 1.15±0.34%, mean+SD, P<0.01). In the adenomas from DMH-treated K-rasVal12 mice, K-rasVal12 transgene recombination and expression were confirmed and shown to promote strong Erk and mild Akt activation compared with adenomas from DMH-treated wild-type mice. Microarray hybridization and cluster analysis demonstrated different expression profiles in adenomas from DMH-treated wild-type and DMH-treated K-rasVal12 mice, indicating involvement of different molecular mechanisms, but array-comparative genomic hybridisation analysis showed chromosome stability in both, with very few chromosome alterations observed in adenomas from either of the two groups. Taken together, these data show that mutant K-ras promotes DMH-induced colorectal tumourigenesis, conferring a proliferative effect, but does not alter chromosome stability in the tumours.

Project description:K-ras mutations are observed in around 40% human colorectal adenomas and carcinomas and contribute to the pathogenesis of human and rodent colorectal tumour formation. Previously, we developed and characterised a strain of transgenic mice with inducible intestinal epithelial expression of K-rasVal12 via a Cre/LoxP system. To evaluate the influence of mutant K-ras on carcinogen-induced colorectal tumourigenesis, we induced neoplastic alterations in the large intestines of wild-type and K-rasVal12 mice using the colon-selective carcinogen 1, 2-dimethylhydrazine (DMH), which has been widely used to study chemically induced colorectal tumours that are histopathologically similar to those observed in humans. K-rasVal12 expression significantly promoted DMH-induced colorectal tumourigenesis: the average life span of the mice decreased from 38.52Â±1.97 weeks for 40 wild-type mice to 32.42Â±2.17 weeks for 26 K-rasVal12 mice (mean+SEM, P<0.05) and the large intestinal tumours increased from 2.27Â±0.15 per wild-type mouse to 3.85Â±0.20 in K-rasVal12 mice (mean+SEM, P<0.01). Adenomas from DMH-treated K-rasVal12 mice showed significantly higher levels (10.9Â±1.69%) of Ki-67-positive proliferating cells compared with those from DMH-treated wild-type mice (7.77Â±1.15%) (mean+SD, P<0.01) and a mild increase in apoptotic nuclei staining for cleaved caspase-3 (1.94+0.51% compared with 1.15Â±0.34%, mean+SD, P<0.01). In the adenomas from DMH-treated K-rasVal12 mice, K-rasVal12 transgene recombination and expression were confirmed and shown to promote strong Erk and mild Akt activation compared with adenomas from DMH-treated wild-type mice. Microarray hybridization and cluster analysis demonstrated different expression profiles in adenomas from DMH-treated wild-type and DMH-treated K-rasVal12 mice, indicating involvement of different molecular mechanisms, but array-comparative genomic hybridisation analysis showed chromosome stability in both, with very few chromosome alterations observed in adenomas from either of the two groups. Taken together, these data show that mutant K-ras promotes DMH-induced colorectal tumourigenesis, conferring a proliferative effect, but does not alter chromosome stability in the tumours. This study has 7 samples analysed, 4 Kras mutants and 3 controls, on the Illumina Mouse-6 Beadchip array.

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Gene expression profile of calcium mediated prevention of colorectal cancer in a mouse model

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