Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Δ716 Cdx2+/- compound mutant mice
Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Δ716 Cdx2+/- compound mutant mice
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DOI：
10.1038/ng1265
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发表时间：
2003-12-01
期刊：
影响因子：
30.8
通讯作者：
Taketo, MM
中科院分区：
文献类型：
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作者：
Aoki, K;Tamai, Y;Taketo, MM
哺乳动物同源框转录因子CDX2在肠道发育和分化中起关键作用。杂合子Cdx2小鼠在近端结肠形成1个或2个良性错构瘤，而杂合子Apc(Δ716)小鼠形成大量腺瘤性息肉，主要在小肠。在此我们表明，Apc(+/Δ716) Cdx2(+/-)复合突变小鼠的结肠息肉数量大约高6倍。APC和CDX2的水平在远端结肠均显著降低，这导致高后期桥指数（ABI）以及Apc位点杂合性缺失（LOH）频率升高。在培养的大鼠肠上皮细胞和人结肠癌细胞系中，反义RNA对CDX2的抑制导致ABI和染色体畸变显著增加。这是由mTOR通路的激活所介导的，导致翻译失调和G₁ - S期加速，伴有p27水平降低以及细胞周期蛋白E - Cdk2的激活。我们在Apc(+/Δ716) Cdx2(+/-)复合突变小鼠的结肠黏膜中获得了类似结果。通过上游调节因子Akt对mTOR的强制激活也增加了结肠癌细胞中的ABI。所有细胞系中的高ABI都可被mTOR抑制剂LY294002和雷帕霉素所抑制。这些结果表明，CDX2表达降低通过mTOR介导的染色体不稳定性在结肠肿瘤发生中起重要作用。
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.