E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer
E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer
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DOI：
10.1038/sj.onc.1209946
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发表时间：
2006-10-19
期刊：
影响因子：
8
通讯作者：
Simon, R.
中科院分区：
文献类型：
--
作者：
Oeggerli, M.;Schraml, P.;Simon, R.
6p 22的扩增发生在约10-20%的膀胱癌中，并且与增强的肿瘤细胞增殖相关。6p 22扩增子的候选靶基因包括E2 F3和相邻基因NM_017774。为了阐明哪个基因代表主要靶标，我们比较了扩增的普遍性和两个基因的功能作用。在由2317例膀胱癌样本组成的膀胱癌组织微阵列上，通过荧光原位杂交分析E2 F3和NM_017774的扩增。这两种基因在893个可解释的肿瘤中的104个（11.6%）中显示扩增，并且仅发现共扩增。在12个肿瘤来源的细胞系中通过实时聚合酶链反应进行的另外的基因表达分析揭示，6p 22的扩增总是与E2 F3和NM_017774的共过表达相关。此外，使用RNA干扰来研究基因表达降低对细胞生长的影响。在具有和不具有6p 22扩增子的肿瘤细胞中，E2 F3的敲低总是导致明确的增殖减少，而NM_017774的敲低仅能够减缓非扩增细胞中的细胞增殖。我们的研究结果指出，E2 F3而不是NM_017774驱动6p 22扩增的肿瘤细胞的增殖增强。我们的结论是，E2 F3必须负责6p 22扩增膀胱癌细胞的生长优势。
Amplification of 6p22 occurs in about 10-20% of bladder cancers and is associated with enhanced tumour cell proliferation. Candidate target genes for the 6p22 amplicon include E2F3 and the adjacent gene NM_017774. To clarify which gene is representing the main target, we compared the prevalence of the amplification and the functional role of both genes. Ampli.cation of E2F3 and NM_017774 was analysed by fluorescence in situ hybridization on a bladder cancer tissue microarray composed of 2317 cancer samples. Both genes showed amplification in 104 of 893 (11.6%) interpretable tumours and were exclusively found co-amplified. Additional gene expression analysis by real-time polymerase chain reaction in 12 tumour-derived cell lines revealed that amplification of 6p22 was always associated with co-overexpression of E2F3 and NM_017774. Furthermore, RNA interference was used to study the influence of reduced gene expression on cell growth. In tumour cells with and without the 6p22 amplicon, knockdown of E2F3 always lead to unequivocal reduction of proliferation, whereas knockdown of NM_017774 was only capable to slow down cell proliferation in non-amplified cells. Our findings point out that E2F3 but not NM_017774 is driving enhanced proliferation of 6p22 amplified tumour cells. We conclude that E2F3 must be responsible for the growth advantage of 6p22 amplified bladder cancer cells.