Expression of the mitotic checkpoint gene MAD2L2 has prognostic significance in colon cancer
Expression of the mitotic checkpoint gene MAD2L2 has prognostic significance in colon cancer
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DOI：
10.1002/ijc.22155
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发表时间：
2007-01-01
影响因子：
6.4
通讯作者：
Janssen, Klaus-Peter
中科院分区：
文献类型：
--
作者：
Rimkus, Caroline;Friederichs, Jan;Janssen, Klaus-Peter
非整倍体和遗传不稳定性是结直肠癌和其他实体瘤的标志，它们被认为会促进肿瘤进展。基因MAD 2L 2（有丝分裂阻滞缺陷2-样2）编码纺锤体检查点蛋白MAD 2L 2（或MAD 2B），这是一个监视系统的关键组成部分，可以延迟后期，直到所有染色体都正确定向。已知这种有丝分裂检查点的缺陷会导致遗传不稳定性，即，染色体数目和结构畸变。我们先前已经通过基因表达谱鉴定了MAD 2L 2在局部限制性结直肠肿瘤中显著上调。到目前为止，MAD 2L 2还没有被报道在人类癌症中发挥重要作用，而其同源物MAD 2。为了解决这个问题，我们通过实时定量PCR分析了118例组织学证实的结直肠病变的MAD 2L 2表达，并与11例患者的正常结肠组织进行了比较。与正常结肠相比，118个肿瘤样品中的25个（21%）显示MAD 2L 2过表达3倍或更多，并且过表达肿瘤的分数随着肿瘤分期而增加。相应地，发现与匹配的正常组织相比，MAD 2L 2的蛋白水平在肿瘤中显著上调。MAD 2L 2表达上调的肿瘤具有显著更高数量的异常有丝分裂像（后期桥），这是染色体不稳定性的指示。MAD 2L 2的表达升高与患者生存率降低显著相关。通过多变量分析，MAD 2L 2表达被保留为患者生存的独立预后参数。因此，我们的研究结果表明，MAD 2L 2的过度表达与结直肠癌的不良预后相关。(c)2006威利-利斯公司
Aneuploidy and genetic instability are a hallmark of colorectal cancer and other solid tumors, and they are thought to enhance tumor progression. The gene MAD2L2 (mitotic arrest deficient 2-like 2) encodes the spindle checkpoint protein MAD2L2 (or MAD2B), a key component of a surveillance system that delays anaphase until all chromosomes are correctly oriented. Defects in this mitotic checkpoint are known to contribute to genetic instability, i.e., numerical and structural aberrations of chromosomes. We have previously identified MAD2L2 as significantly upregulated in locally restricted colorectal tumors by gene expression profiling. So far, MAD2L2 has not been reported to play a major role in human cancer in contrast to its homologue MAD2. To address this question, 118 histologically confirmed colorectal lesions were analyzed by quantitative real-time PCR for expression of MAD2L2, and compared to normal colon tissue from 11 patients. Twenty-five out of 118 tumor samples (21%) showed MAD2L2 overexpression of 3-fold or more compared to normal colon, and the fraction of overexpressing tumors increased with tumor stage. Correspondingly, protein levels of MAD2L2 were found to be significantly upregulated in tumors as compared to matched normal tissue. Tumors with upregulated MAD2L2 expression had significantly higher numbers of aberrant mitotic figures (anaphase bridges), an indication of chromosomal instability. Elevated expression of MAD2L2 was significantly correlated with reduced patient survival. By multivariate analysis, MAD2L2 expression was retained as an independent prognostic parameter for patient survival. Thus, our results demonstrate that overexpression of MAD2L2 correlates with bad prognosis in colorectal cancer. (c) 2006 Wiley-Liss, Inc.