CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients

J Clin Invest. 2010 Apr;120(4):1178-91. doi: 10.1172/JCI40665. Epub 2010 Mar 24.


Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified oncogene localized at 1q21, a frequently amplified region in hepatocellular carcinoma (HCC). To explore its oncogenic mechanisms, we set out to identify CHD1L-regulated genes using a chromatin immunoprecipitation-based (ChIP-based) cloning strategy in a human HCC cell line. We then further characterized 1 identified gene, ARHGEF9, which encodes a specific guanine nucleotide exchange factor (GEF) for the Rho small GTPase Cdc42. Overexpression of ARHGEF9 was detected in approximately half the human HCC samples analyzed and positively correlated with CHD1L overexpression. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition (EMT) via ARHGEF9-mediated Cdc42 activation. Silencing ARHGEF9 expression by RNAi effectively abolished the invasive and metastatic abilities of CHD1L in mice. Furthermore, investigation of clinical HCC specimens showed that CHD1L and ARHGEF9 were markedly overexpressed in metastatic HCC tissue compared with healthy tissue. Increased expression of CHD1L was often observed at the invasive front of HCC tumors and correlated with venous infiltration, microsatellite tumor nodule formation, and poor disease-free survival. These findings suggest that CHD1L-ARHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / etiology*
  • Carcinoma, Hepatocellular / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement
  • DNA Helicases / physiology*
  • DNA-Binding Proteins / physiology*
  • Disease Progression
  • Endothelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Liver Neoplasms / etiology*
  • Liver Neoplasms / pathology
  • Male
  • Mesoderm / pathology
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Rho Guanine Nucleotide Exchange Factors
  • cdc42 GTP-Binding Protein / metabolism


  • ARHGEF9 protein, human
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Rho Guanine Nucleotide Exchange Factors
  • DNA Helicases
  • CHD1L protein, human
  • cdc42 GTP-Binding Protein