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首页> 外文期刊>Cell cycle >Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells
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Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells

机译：四倍体作用促进人类细胞染色体的不稳定性，对有丝分裂错误的耐受性和多药耐药性

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Up to 80% of human cancers, in particular solid tumors, contain cells with abnormal chromosomal numbers, or aneuploidy, which is often linked with marked chromosomal instability. Whereas in some tumors the aneuploidy occurs by missegregation of one or a few chromosomes, aneuploidy can also arise during proliferation of inherently unstable tetraploid cells generated by whole genome doubling from diploid cells. Recent findings from cancer genome sequencing projects suggest that nearly 40% of tumors underwent whole genome doubling at some point of tumorigenesis, yet its contribution to cancer phenotypes and benefits for malignant growth remain unclear. Here, we investigated the consequences of a whole genome doubling in both cancerous and non-transformed p53 positive human cells. SNP array analysis and multicolor karyotyping revealed that induced whole-genome doubling led to variable aneuploidy. We found that chromosomal instability (CIN) is a frequent, but not a default outcome of whole genome doubling. The CIN phenotypes were accompanied by increased tolerance to mitotic errors that was mediated by suppression of the p53 signaling. Additionally, the expression of pro-apoptotic factors, such as iASPP and cIAP2, was downregulated. Furthermore, we found that whole genome doubling promotes resistance to a broad spectrum of chemotherapeutic drugs and stimulates anchorage-independent growth even in non-transformed p53-positive human cells. Taken together, whole genome doubling provides multifaceted benefits for malignant growth. Our findings provide new insight why genome-doubling promotes tumorigenesis and correlates with poor survival in cancer.
机译：多达80％的人类癌症（尤其是实体瘤）包含具有异常染色体数或非整倍性的细胞，这通常与明显的染色体不稳定性相关。在某些肿瘤中，非整倍性是由于一个或几个染色体的错聚而发生的，而非整倍性也可能发生在由二倍体细胞加倍的全基因组产生的内在不稳定的四倍体细胞的增殖过程中。癌症基因组测序项目的最新发现表明，近40％的肿瘤在肿瘤发生的某个时间点进行了全基因组加倍，但是其对癌症表型的贡献以及对恶性肿瘤生长的益处尚不清楚。在这里，我们研究了在癌和未转化的p53阳性人类细胞中整个基因组加倍的后果。 SNP阵列分析和多色核型分析表明，诱导的全基因组加倍导致可变的非整倍性。我们发现染色体不稳定性（CIN）是一个频繁发生的现象，但不是整个基因组加倍的默认结果。 CIN表型伴随着对有丝分裂错误的耐受性增强，该耐受性是通过抑制p53信号传导介导的。另外，促凋亡因子如iASPP和cIAP2的表达被下调。此外，我们发现整个基因组加倍促进了对广泛的化疗药物的耐药性，甚至在未转化的p53阳性人类细胞中也刺激了锚定非依赖性生长。综上所述，全基因组加倍为恶性生长提供了多方面的好处。我们的发现提供了新的见解，说明为什么基因组加倍促进肿瘤发生并与癌症的不良生存相关。

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