The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer†
The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer†
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DOI：
10.1093/hmg/ddp034
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Sanchez-Cespedes, Montse
中科院分区：
文献类型：
--
作者：
Medina, Pedro P.;Castillo, Sandra D.;Sanchez-Cespedes, Montse
癌基因的寻找在癌症遗传学中正变得越来越重要，因为它们是治疗干预的合适靶点。为了确定新的癌基因，通过基因扩增激活，我们通过高分辨率比较基因组杂交分析了cDNA微阵列，并比较了肺癌细胞系的DNA拷贝数和mRNA表达水平。我们鉴定了几个扩增子(5p13、6p22-21、11q13、17q21和19q13)，它们伴随着基因表达的增加。这些区域也被发现在肺原发肿瘤中被放大。我们绘制了染色体6p扩增子内的边界并测量了基因的表达水平。Sry-HMG box基因Sox4(性别决定区Y box 4)编码一种参与胚胎细胞分化的转录因子，在扩增的细胞中比正常细胞高表达10倍。SOX4在部分肺原发肿瘤和肺癌细胞系中的表达也较强，并与基因扩增的存在有关。我们还在肺原发肿瘤和癌细胞系中发现了Sox4的变体，包括在富含丝氨酸的C末端区域引入过早终止密码子(S395X)的体细胞突变。虽然所有突变体都没有增加Sox4的反式激活能力，但野生型和非截短突变体在NIH3T3细胞中的过表达显著增加了弱致癌RHOA-Q63L的转化能力。总之，我们的结果表明，在肺癌中，由于基因扩增，Sox4过表达，并为Sox4的致癌特性提供了证据。
The search for oncogenes is becoming increasingly important in cancer genetics because they are suitable targets for therapeutic intervention. To identify novel oncogenes, activated by gene amplification, we analyzed cDNA microarrays by high-resolution comparative genome hybridization and compared DNA copy number and mRNA expression levels in lung cancer cell lines. We identified several amplicons (5p13, 6p22-21, 11q13, 17q21 and 19q13) that had a concomitant increase in gene expression. These regions were also found to be amplified in lung primary tumours. We mapped the boundaries and measured expression levels of genes within the chromosome 6p amplicon. The Sry-HMG box gene SOX4 (sex-determining region Y box 4), which encodes a transcription factor involved in embryonic cell differentiation, was overexpressed by a factor of 10 in cells with amplification relative to normal cells. SOX4 expression was also stronger in a fraction of lung primary tumours and lung cancer cell lines and was associated with the presence of gene amplification. We also found variants of SOX4 in lung primary tumours and cancer cell lines, including a somatic mutation that introduced a premature stop codon (S395X) at the serine-rich C-terminal domain. Although none of the variants increased the transactivation ability of SOX4, overexpression of the wildtype and of the non-truncated variants in NIH3T3 cells significantly increased the transforming ability of the weakly oncogenic RHOA-Q63L. In conclusion, our results show that, in lung cancer, SOX4 is overexpressed due to gene amplification and provide evidence of oncogenic properties of SOX4.