Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma

Oncogene. 2008 Sep 18;27(42):5578-89. doi: 10.1038/onc.2008.168. Epub 2008 May 26.


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 profiling, binding site computation and empirical verification 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Chromatin Immunoprecipitation
  • Gene Expression Profiling
  • Humans
  • Liver Neoplasms / pathology*
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neuropilin-1 / genetics
  • Oligonucleotide Array Sequence Analysis / methods*
  • Phylogeny
  • RNA, Small Interfering / genetics
  • SOXC Transcription Factors / antagonists & inhibitors
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / physiology*
  • Semaphorins / genetics


  • RNA, Small Interfering
  • SOX4 protein, human
  • SOXC Transcription Factors
  • Sema3C protein, human
  • Semaphorins
  • Neuropilin-1