Induction Of Renal Tumorigenesis With Elevated Levels Of Somatic Loss Of Heterozygosity In Tsc1(+/-) Mice On A Blm-Deficient Background
CANCER RESEARCH(2005)
摘要
A Bloom's deficient mouse model (Blm(m3/m3)) has been shown to induce colorectal tumorigenesis when crossed with Apc(+/Min),, mice. Here, we investigated whether the Blm(m3/m3) genotype could induce tumorigenesis in extracolonic tissues in tuberous sclerosis 1-deficient (Tscl(+/-)) mice that are predisposed to renal cystadenomas and carcinomas. Genotyping of offspring from Tscl(+/-) Blm(+/m3) intercrosses showed that a similar to 24% excess of Tscl(+/-) over Tscl(+/+) mice died before weaning (P = 0.016), although Blm deficiency had no cumulative effect on Tscl(+/-) survival. Tscl(+/-) Blm(m3/m3),3 mice had significantly more macroscopic and microscopic renal lesions at 3 to 6 months compared with Tscl(+/-) Blm(+/m3) mice (P =0.0003 and 0.0203, respectively), and their tumors showed significantly increased levels of somatic loss of heterozygosity (LOH) of the wild-type Tscl (Tsel(wt)) allele compared with those from Tscl(+/-) Blm(+/+) mice (P < 0.0001). Tscl(+/-) Blm(+/m3) mice did not show significantly more renal lesions compared with Tscl(+/-) Blm(+/+) animals; however, their lesions still showed significantly increased levels of somatic LOH of the Tsel(wt) allele (P = 0.03). Ninety-five percent (19 of 20) of lesions from Tscl(+/-) Blm(+/m3),3 mice retained the wild-type Blm (Blm(wt)) allele, indicating that the increased somatic LOH at Tscl was mediated by Blm haploinsufficiency. Renal lesions from a Blm-deficient background stained positively with anti-phospho-S6 ribosomal protein (Ser(240/244)), suggesting that these lesions develop through the normal pathway of Tsc-associated tumorigenesis. This work shows the use of the Blm(m3/m3) mice for inducing renal tumorigenesis, and the high levels (similar to 87%) of LOH in the resultant tumors will help facilitate mapping of loci involved in tumor progression.
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关键词
wild type,cumulant,loss of heterozygosity,ribosomal protein
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