Journal
ONCOGENE
Volume 27, Issue 42, Pages 5578-5589Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.168
Keywords
SOX4; HCC metastasis; synexpression; target prediction
Funding
- National Research Program for Genomic Medicine (NRPGM)
- National Science Council
- National Research Program for Genomic Medicine [NSC 94-3112-B-001-003, NSC 94-3112-B-001-018-Y]
- National Science Council [NSC 95-2752-B-010-002-PAE]
- Ministry of Education
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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.
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