Aberrant Wnt/β-catenin signaling can induce chromosomal instability in colon cancer
Aberrant Wnt/β-catenin signaling can induce chromosomal instability in colon cancer
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DOI：
10.1073/pnas.0604206103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Behrens, Juergen
中科院分区：
文献类型：
--
作者：
Hadjihannas, Michel V.;Brueckner, Martina;Behrens, Juergen
染色体不稳定性（CIN）是大多数结肠肿瘤的标志，可通过增加遗传畸变率促进肿瘤进展。CIN被认为是不适当的有丝分裂和纺锤体检查点活性的结果，但其分子基础在很大程度上仍然难以捉摸。大多数结肠肿瘤的发展是由于肿瘤抑制因子AIPC的突变，导致Wnt/β-连环蛋白信号转导激活和随后的靶基因转录，包括传导蛋白/AXIN 2。在这里，我们证明了Wnt/β-catenin信号通过上调传导蛋白导致CIN。有CIN的人结肠肿瘤样品显示出比没有CIN的人结肠肿瘤样品显著更高的传导蛋白表达。传导蛋白在有丝分裂过程中上调，沿着结肠癌细胞的有丝分裂纺锤体定位，并与polo样激酶1结合。在染色体稳定的结肠癌细胞中，conductin的异位表达或通过小干扰RNA介导的APC敲低上调导致CIN。高conductin表达妥协的纺锤体检查点，这需要本地化的polo样激酶I活性。通过在结肠癌细胞中用小干扰RNA敲低传导蛋白或在小鼠胚胎成纤维细胞中进行基因消融来执行检查点。
Chromosomal instability (CIN), a hallmark of most colon tumors, may promote tumor progression by increasing the rate of genetic aberrations. CIN is thought to arise as a consequence of improper mitosis and spindle checkpoint activity, but its molecular basis remains largely elusive. The majority of colon tumors develop because of mutations in the tumor suppressor AIPC that lead to Wnt/beta-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2. Here we demonstrate that Wnt/beta-catenin signaling causes CIN via up-regulation of conductin. Human colon tumor samples with CIN show significantly higher expression of conductin than those without. Conductin is up-regulated during mitosis, localizes along the mitotic spindles of colon cancer cells, and binds to polo-like kinase 1. Ectopic expression of conductin or its up-regulation through small interfering RNA-mediated knock-down of APC leads to CIN in chromosomally stable colon cancer cells. High conductin expression compromises the spindle checkpoint, and this requires localized polo-like kinase I activity. Knock-down of conductin by small interfering RNA in colon carcinoma cells or gene ablation in mouse embryo fibroblasts enforces the checkpoint.