Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines
Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines
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DOI：
10.1038/sj.onc.1208119
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发表时间：
2004-12-02
期刊：
影响因子：
8
通讯作者：
Cheung, ALM
中科院分区：
文献类型：
--
作者：
Deng, W;Tsao, SW;Cheung, ALM
染色体异常在癌症中很常见。然而，对导致特定实体肿瘤发生的染色体异常的研究一直受到严重阻碍，因为大多数实体肿瘤具有复杂的染色体异常，在相同的肿瘤类型中不同。类似的现象也存在于永生化细胞系中。驱动这些不同像差的潜在机制在很大程度上是未知的。端粒在保护真核染色体的完整性和维持人类细胞基因组的稳定性方面起着至关重要的作用。正常人体细胞单个染色体上的端粒长度是不均匀的，并随着年龄的增长而逐渐缩短。本研究首次成功地应用分子细胞遗传学方法，对同一人类中期染色体进行了连续端粒定量荧光原位杂交和光谱核型分析，研究了处于永生化状态的多个人类细胞系中个体端粒缩短的动态变化及其与染色体异常的关系。HPV16E6和E7的表达使人卵巢表面上皮细胞和食道上皮细胞永生化，并通过失活P53和Rb基因来驱动细胞增殖。在这些细胞系中，我们一致地检测到端粒信号强度的大规模差异，不仅在非同源染色体臂之间，而且在一些同源染色体臂之间。来自不同捐赠者的细胞系具有不同的端粒曲线(缺乏端粒信号)。值得注意的是，在多个永生化细胞系中，染色体结构异常的不同分布与全基因组中临界短端粒的不同分布有高度显著的相关性。由于细胞永生化是癌症的标志之一，我们的发现表明，不同人类个体中不同类型的临界短端粒可能在确定人类实体瘤中复杂的和个体特有的染色体结构异常方面发挥重要作用。
Chromosomal aberrations are common in cancers. However, the search for chromosomal aberrations leading to development of specific solid tumors has been severely hindered because the majority of solid tumors have complex chromosomal aberrations that differ within the same tumor types. A similar phenomenon exists in immortalized cell tines. The underlying mechanisms driving these diverse aberrations are largely unknown. Telomeres play crucial roles in protecting the integrity of eucaryotic chromosomes and maintaining genomic stability of human cells. Telomere lengths on individual chromosomes in normal human somatic cells are heterogeneous and undergo progressive shortening with aging process. In this study, for the first time, a molecular cytogenetic method using sequential telomere quantitative fluorescence in situ hybridization and spectral karyotyping on the same human metaphases was applied successfully to examine the dynamic profiles of individual telomere shortening and their relationship to chromosome aberrations in multiple human cell lines undergoing immortalization. Human ovarian surface epithelial cells and esophageal epithetial cells were immortalized by the expression of HPV16 E6 and E7, which drive cells to proliferate by inactivating p53 and Rb genes. In these cell lines, we consistently detected large-scale differences in telomere signal intensities not only among nonhomologous chromosome arms but also between some homologous chromosome arms. The cell lines derived from different donors had different profiles of critically short telomeres (lacking telomere signals). Strikingly, the different profiles of chromosomal structural aberrations in multiple immortalized cell lines were highly significantly associated with the distinct distributions of critically short telomeres in whole-genome. Since cellular immortalization is one of the hallmarks of cancer, our findings suggest that distinct profiles of critically short telomeres in different human individuals might play an essential role in determining the complex and individual-specific chromosomal structural aberrations in human solid tumors.