Transfer of chromosome 3 fragments suppresses tumorigenicity of an ovarian cancer cell line monoallelic for chromosome 3p
Transfer of chromosome 3 fragments suppresses tumorigenicity of an ovarian cancer cell line monoallelic for chromosome 3p
复制标题
DOI：
10.1038/sj.onc.1209821
复制
发表时间：
2007-01-25
期刊：
影响因子：
8
通讯作者：
Tonin, P. N.
中科院分区：
文献类型：
--
作者：
Cody, N. A. L.;Ouellet, V.;Tonin, P. N.
多染色体3 p肿瘤抑制基因（TSG）已被提出在卵巢癌的发病机制的基础上的复杂模式的3 p丢失。为了获得支持TSGs的功能证据并确定候选区域，我们应用了染色体转移方法，该方法涉及致瘤性OV 90人卵巢癌细胞系的细胞融合，3 p的单等位基因和含有人3号染色体的辐照小鼠细胞系，以获得含有正常3 p片段的OV 90杂交体。所得的杂交体在裸鼠异种移植试验中显示出完全或不完全的致瘤性抑制，并且以与其体内致瘤表型的改变一致的方式在软琼脂糖和三维球状体中形成集落的能力不同。表达微阵列分析确定了一组常见的差异表达基因，如VEGF，DAB 2和VEGF，其中一些已被证明与卵巢癌有关。基因分型分析显示，他们窝藏正常的3 p片段，其中一些重叠的候选TSG区域（3 p25 p26，3 p24和3 p14-pcen）先前确定的卵巢癌杂合性丢失分析。然而，只有3 p12-pcen区域是获得共同的所有杂交，表达微阵列分析确定差异表达的基因。3 p12 peen转移和肿瘤抑制与细胞转录组的协同重编程的相关性表明，假定的TSG可能影响了卵巢癌的关键潜在事件。
Multiple chromosome 3p tumor suppressor genes (TSG) have been proposed in the pathogenesis of ovarian cancer based on complex patterns of 3p loss. To attain functional evidence in support of TSGs and identify candidate regions, we applied a chromosome transfer method involving cell fusions of the tumorigenic OV90 human ovarian cancer cell line, monoallelic for 3p and an irradiated mouse cell line containing a human chromosome 3 in order to derive OV90 hybrids containing normal 3p fragments. The resulting hybrids showed complete or incomplete suppression of tumorigenicity in nude mouse xenograft assays, and varied in their ability to form colonies in soft agarose and three-dimensional spheroids in a manner consistent with alteration of their in vivo tumorigenic phenotypes. Expression microarray analysis identified a set of common differentially expressed genes, such as SPARC, DAB2 and VEGF, some of which have been shown implicated in ovarian cancer. Genotyping assays revealed that they harbored normal 3p fragments, some of which overlapped candidate TSG regions (3p25p26, 3p24 and 3p14-pcen) identified previously in loss of heterozygosity analyses of ovarian cancers. However, only the 3p12-pcen region was acquired in common by all hybrids where expression microarray analysis identified differentially expressed genes. The correlation of 3p12peen transfer and tumor suppression with a concerted reprogramming of the cellular transcriptome suggest that the putative TSG may have affected key underlying events in ovarian cancer.