Analysis of centrosome overduplication in correlation to cell division errors in high-risk human papillomavirus (HPV)-associated anal neoplasms
Analysis of centrosome overduplication in correlation to cell division errors in high-risk human papillomavirus (HPV)-associated anal neoplasms
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DOI：
10.1016/j.virol.2007.10.030
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发表时间：
2008-03-01
期刊：
影响因子：
3.7
通讯作者：
Duensing, Stefan
中科院分区：
文献类型：
--
作者：
Duensing, Anette;Chin, Anna;Duensing, Stefan
高危HPV相关肛门肿瘤难以治疗，需要恶性进展的生物标志物。致癌进展的一个标志是基因组不稳定性，这通常与细胞分裂错误和非整倍体有关。HPV-16 E7癌蛋白先前已显示快速诱导中心粒和中心体过度复制，并与HPV-16 E6协同诱导异常多极有丝分裂。基于这种功能，有人认为HPV-16 E7可能是染色体不稳定的驱动力。然而，到目前为止，尚未对原发性HPV相关肿瘤中的中心体过度复制进行详细分析。在这里，我们使用最近发现的成熟母体中心粒标记物Cep 170确定了HPV相关肛门病变中中心体过度重复的频率。我们在一小部分但很重要的细胞中检测到中心体过度复制。值得注意的是，中心体过度复制，而不是异常的中心体数目本身或中心体积累，与细胞分裂错误的存在显着相关。此外，我们的实验表明，特别是假双极有丝分裂可能在高危HPV相关肿瘤中染色体不稳定性的传播中发挥作用。这些结果为中心体畸变在细胞分裂错误中的作用提供了新的见解，并鼓励进一步研究中心体过度复制作为HPV相关肛门病变恶性进展的预测生物标志物。(C)2007爱思唯尔公司All rights reserved.
High-risk HPV-associated anal neoplasms are difficult to treat and biomarkers of malignant progression are needed. A hallmark of carcinogenic progression is genomic instabitity, which is frequently associated with cell division errors and aneuploidy. The HPV-16 E7 oncoprotein has been previously shown to rapidly induce centriole and centrosome overduplication and to cooperate with HPV-16 E6 in the induction of abnormal multipolar mitoses. Based on this function, it has been suggested that HPV-16 E7 may act as a driving force for chromosomal instability. However, a detailed analysis of centrosome overduplication in primary HPV-associated neoplasms has not been performed so far. Here, we determined the frequency of centrosome overduplication in HPV-associated anal lesions using a recently identified marker for mature maternal centrioles, Cep 170. We detected centrosome overduplication in a small but significant fraction of cells. Remarkably, centrosome overduplication, but not aberrant centrosome numbers per se or centrosome accumulation, correlated significantly with the presence of cell division errors. In addition, our experiments revealed that in particular pseudo-bipolar mitoses may play a role in the propagation of chromosomal instability in high-risk HPV-associated tumors. These results provide new insights into the role of centrosome aberrations in cell division errors and encourage further studies on centrosome overduplication as a predictive biomarker of malignant progression in HPV-associated anal lesions. (C) 2007 Elsevier Inc. All rights reserved.