Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma
Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma
复制标题
DOI：
10.1038/onc.2008.168
复制
发表时间：
2008-09-18
期刊：
影响因子：
8
通讯作者：
Tsou, A-P
中科院分区：
文献类型：
--
作者：
Liao, Y-L;Sun, Y-M;Tsou, A-P
一项全面的肝细胞癌基因芯片分析揭示了肝内转移过程中不同的共表达模式。最近的证据表明，共表达的群体成员基因很可能受主控基因(S)的调控。在这里，我们研究了转录因子Sox4在肝内转移性肝癌中的功能和基因调控。SOX4在肿瘤转移中起重要作用，因为RNAi敲除减少了肿瘤细胞的迁移、侵袭、体内肿瘤的形成和转移。整合基因亲的多方面方法。Ling，结合位的计算和经验验证。通过染色质免疫沉淀和基因消融，提纯了Sox4的共同结合基序，并在31个基因中鉴定了32个结合位点，可信度很高。RNAi敲除了两个Sox4靶基因，Neuropilin 1和Signaphorin 3C，显著降低了肝癌细胞系的细胞迁移活性，表明Sox4通过调节这两个下游靶点发挥部分作用。31个以前未知的靶点的发现扩大了我们对Sox4如何调控肝癌进展的了解，并暗示了一系列新的Sox4功能。这种集成的方法建立了一种范例，即来自共表达组的成员基因的子集可以由一个主控制基因来调节，这以SOX4和晚期肝癌为例。
A comprehensive microarray analysis of hepatocellular carcinoma (HCC) revealed distinct synexpression patterns during intrahepatic metastasis. Recent evidence has demonstrated that synexpression group member genes are likely to be regulated by master control gene(s). Here we investigate the functions and gene regulation of the transcription factor SOX4 in intrahepatic metastatic HCC. SOX4 is important in tumor metastasis as RNAi knockdown reduces tumor cell migration, invasion, in vivo tumorigenesis and metastasis. A multifaceted approach integrating gene pro. ling, binding site computation and empirical veri. cation by chromatin immunoprecipitation and gene ablation refined the consensus SOX4 binding motif and identified 32 binding loci in 31 genes with high confidence. RNAi knockdown of two SOX4 target genes, neuropilin 1 and semaphorin 3C, drastically reduced cell migration activity in HCC cell lines suggesting that SOX4 exerts some of its action via regulation of these two downstream targets. The discovery of 31 previously unidentified targets expands our knowledge of how SOX4 modulates HCC progression and implies a range of novel SOX4 functions. This integrated approach sets a paradigm whereby a subset of member genes from a synexpression group can be regulated by one master control gene and this is exemplified by SOX4 and advanced HCC.