Trisomy represses ApcMin-mediated tumours in mouse models of Down's syndrome
Trisomy represses ApcMin-mediated tumours in mouse models of Down's syndrome
复制标题
DOI：
10.1038/nature06446
复制
发表时间：
2008-01-03
期刊：
影响因子：
64.8
通讯作者：
Reeves, Roger H.
中科院分区：
文献类型：
--
作者：
Sussan, Thomas E.;Yang, Annan;Reeves, Roger H.
关于21三体（唐氏综合征）患者实体瘤发病率是否较低，跨越50多年的流行病学研究得出了相互矛盾的结论（1,2）。我们使用唐氏综合症和癌症的小鼠模型，以生物学方法研究三体和肠道肿瘤发病率之间的关系。在非整倍体小鼠模型Ts65Dn、Ts1Rhr和Ms1Rhr中测定Apc（Min）介导的肿瘤数量。在Ts65Dn小鼠中，大约一半的21号染色体基因（Hsa21）的同源基因的三体，或Ts1Rhr小鼠中只有33个这些基因的三体，导致肠道肿瘤的数量显著减少。在Ms1Rhr中，相同的33个基因的片段单体在Ts1Rhr中复制三倍，导致肿瘤数量增加。进一步的研究表明，Ets2基因对肠道肿瘤数量的剂量敏感性起主要作用。当Ets2作为抑制因子过表达时，其作用与肿瘤抑制不同，肿瘤抑制需要正常的基因功能来阻止细胞转化。上调Ets2和潜在的参与这种保护作用的其他基因可能在所有个体中提供预防作用，而不考虑倍性。
Epidemiological studies spanning more than 50 yr reach conflicting conclusions as to whether there is a lower incidence of solid tumours in people with trisomy 21 ( Down's syndrome)(1,2). We used mouse models of Down's syndrome and of cancer in a biological approach to investigate the relationship between trisomy and the incidence of intestinal tumours. Apc(Min)-mediated tumour number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr and Ms1Rhr. Trisomy for orthologues of about half of the genes on chromosome 21 ( Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumours. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumours. Further studies demonstrated that the Ets2 gene contributed most of the dosage- sensitive effect on intestinal tumour number. The action of Ets2 as a repressor when it is overexpressed differs from tumour suppression, which requires normal gene function to prevent cellular transformation. Upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.