Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Δ716 Cdx2+/- compound mutant mice

被引:197
作者
Aoki, K
Tamai, Y
Horiike, S
Oshima, M
Taketo, MM
机构
[1] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan
[2] Banyu Tsukuba Res Inst Merck, Ibaraki 3002611, Japan
[3] Kyoto Prefectural Univ Med, Dept Internal Med 3, Kyoto 6028566, Japan
关键词
D O I
10.1038/ng1265
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The mammalian homeobox transcription factor CDX2 has key roles in intestinal development and differentiation. Heterozygous Cdx2 mice develop one or two benign hamartomas in the proximal colon, whereas heterozygous Apc(Delta716) mice develop numerous adenomatous polyps, mostly in the small intestine. Here we show that the colonic polyp number is about six times higher in Apc(+/Delta716) Cdx2(+/-) compound mutant mice. Levels of both APC and CDX2 were significantly lower in the distal colon, which caused high anaphase bridge index (ABI) associated with a higher frequency of loss of heterozygosity (LOH) at Apc. In cultured rat intestinal epithelial and human colon cancer cell lines, suppression of CDX2 by antisense RNA caused marked increases in ABI and chromosomal aberrations. This was mediated by stimulation of the mTOR pathway, causing translational deregulation and G(1)-S acceleration, associated with low levels of p27 and activation of cyclin E-Cdk2. We obtained similar results in the colonic mucosa of Apc(+/Delta716) Cdx2(+/-) compound mutant mice. Forced activation of mTOR through upstream regulator Akt also increased ABI in colon cancer cells. High ABI in all cell lines was suppressed by mTOR inhibitors LY294002 and rapamycin. These results suggest that reduced expression of CDX2 is important in colon tumorigenesis through mTOR-mediated chromosomal instability.
引用
收藏
页码:323 / 330
页数:8
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